Substituted thienoimidazole derivatives, a process for the preparation thereof, pharmaceutical compositions containing them, and the use thereof as inhibitors of gastric acid secretion, as gastroprotectives and as medicaments for intestinal inflammations

ABSTRACT

Substituted thienoimidazole derivatives, a process for the preparation thereof, pharmaceutical compositions containing them, and the use thereof as inhibitors of gastric acid secretion, as gastroprotectives and as medicaments for intestinal inflammations 
     The invention relates to compounds of the formula ##STR1## in which A represents ##STR2## T denotes --S--, --SO-- or --SO 2  --, R 1  to R 10 , X, Y and Z have the meanings indicated in the description, to a process for the preparation thereof, to pharmaceutical compositions containing them, and to the use thereof as inhibitors of gastric acid secretion, as gastroprotectives and as medicaments for intestinal inflammations.

Benzimidazole derivatives acting to inhibit gastric acid secretion asdisclosed in, for example, DE-A No. 2,548,340, EP-A Nos. 5129, 178,438,198,583 and DE-A No. 3,240,248.

The present invention relates to thienoimidazole derivatives of theformula I ##STR3## in which

A represents ##STR4##

T denotes --S--, --SO-- or --SO₂ --,

R¹ and R² are identical or different and denote hydrogen, halogen,cyano, nitro, trifluoromethyl, (C₁ -C₆)-alkyl, (C₁ -C₆)-hydroxyalkyl,(C₁ -C₆)-alkoxy, (C₁ -C₄)fluoroalkoxy, --OCF₂ Cl--, --O--CF₂ --CHFCl,(C₁ -C₆)alkylmercapto, (C₁ -C₆)-alkylsulfinyl, (C₁ -C₆)alkylsulfonyl,(C₁ -C₆)-alkylcarbonyl, (C₁ -C₆)alkoxycarbonyl, carbamoyl, N-(C₁-C₄)-alkylcarbamoyl, N,N-di-(C₁ -C₄)-alkylcarbamoyl, (C₁-C₆)-alkylcarbonyloxy, (C₃ -C₈)-cycloalkyl, phenyl, benzyl, phenoxy,benzyloxy, anilino, N-methylnilino, phenylmercapto, phenylsulfonyl,phenylsulfinyl, sulfamoyl, N-(C₁ -C₄)-alkylsulfamoyl or N,N-di-(C₁-C₄)-alkylsulfamoyl, or, if A is defined as above under (a) or (c), canalso together denote --[CH_(2--n) -- or --CH═CH--CH═CH--, with one CH₂group optionally being replaced by O, S, SO or SO₂,

R³ denotes hydrogen, alkanoyl, (C₁ -C₆)-alkylcarbamoyl or anotherphysiologically tolerated N^(im) protective group which can preferablybe eliminated in an acid medium and/or under physiological conditions,

R⁴ and R⁵ are identical or different and denote hydrogen or (C₁-C₃)-alkyl,

X denotes nitrogen, and Y denotes CR⁶, or

X denotes CR⁶, and Y denotes nitrogen,

R⁶ denotes hydrogen, halogen, (C₁ -C₆)-alkyl, trifluoromethyl, (C₁-C₆)-alkoxy, --O--C_(p) H.sub.(2p+1-q) F_(q), (C₁ -C₆)alkoxy, (C₁-C₆)-alkyl, (C₆ -C₁₂)-aryl, (C₆ -C₁₂)-aryl(C₁ -C₆)-alkoxy, (C₁-C₉)-heteroaryl, (C₆ -C₁₂)-aryloxy, it being possible for thecorresponding aryl moiety to be optionally substituted by halogen ortrifluoromethyl, or denotes cyano, nitro, (C₁ -C₆)-alkylamino, di-(C₁-C₆)-alkylamino, or amino,

Z denotes NR⁷ R⁸, OR¹⁰ or SR¹⁰,

R⁷ and R⁸ are identical or different and denote hydrogen, (C₁-C₆)-alkyl, (C₆ -C₁₂)-aryl, (C₇ -C₁₃)aralkyl or (C₃ -C₆)-cycloalkyl, orrepresent, together with the nitrogen to which they are bonded,azetidino, pyrrolidino, piperidino, piperazino, morpholino or N-(C₁-C₄)-alkylpiperazino, each of which is optionally substituted by one ortwo identical or different (C₁ -C₆)-alkyl groups,

R⁹ denotes hydrogen, halogen, (C₁ -C₃)-alkyl, (C₁ -C₄)alkoxy, benzyloxyor (C₁ -C₇)-alkoxy-(C₁ -C₃)-alkyl,

R¹⁰ denotes hydrogen, (C₁ -C₄)-alkyl, (C₇ -C₁₃)-aralkyl, (C₆ -C₁₂)-aryl,vinyl, allyl or a substituted alkyl radical of the formula C_(p)H.sub.(2p+1-q) F_(q),

n is 3 or 4,

p is 1, 2, 3 or 4, in particular 2 or 4, and

q is 1 to (2 p+1), in particular 3 to 7, and to the physiologicallytolerated salts thereof.

1H-Thieno[3,4-d]imidazole derivatives of the formula I in which A is asdefined above under (b) are preferred. Further preferred compounds ofthe formula I are those in which R⁹ represents hydrogen. T is preferablyan --SO--group.

Particularly preferred compounds of the formula I are those in which

A is preferably as defined above under (b),

T preferably denotes an --SO-- group,

R¹ and R² are identical or different and denote hydrogen, (C₁-C₃)-alkyl, halogen, (C₁ -C₄)-alkoxy or (C₁ -C₄)alkoxycarbonyl,

R³ is as defined above,

R⁴ and R⁵ each denote hydrogen,

R⁶ denotes amino, hydrogen, halogen, (C₁ -C₆)-alkyl,

(C₁ -C₆)-alkoxy, --O--C_(p) H.sub.(2p+1-q) F_(q), (C₆ -C₁₂)-aryloxy,

(C₆ -C₁₂)-aryl-(C₁ -C₆)-alkoxy, it being possible for the correspondingaryl moiety to be optionally substituted by halogen or trifluoromethyl,or denotes cyano, nitro, (C1-C6)-alkylamino, di-(C₁ -C₆)-alkylamino or(C₁ -C₆)-alkoxy-(C₁ -C₃)-alkyl, with R⁶ particularly being hydrogen,chlorine, (C₁ -C₆)-alkyl, (C₁ -C₆)alkoxy or C_(p) H.sub.(2p+1-q) F_(q),

R⁷ and R⁸ represent, together with the nitrogen to which they arebonded, azetidino, piperazino, pyrrolidino, morpholino, piperidino orN-(C₁ -C₄)-alkylpiperazino, or both denote hydrogen, or R⁷ is hydrogenand R⁸ is a (C₃ -C₆)-cycloalkyl group, but are preferably identical ordifferent and represent hydrogen or (C₁ -C₆)-alkyl or, together,represent piperidino, pyrrolidino, piperazino or morpholino and/or

R⁹ is hydrogen

R¹⁰ denotes hydrogen, (C₁ -C₄)-alkyl, (C₆ -C₁₂)-aryl, (C₇ -C₁₃)-aralkyl,vinyl, allyl, CpH.sub.(2p+1-q) F_(q), with alkyl preferably beingmethyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl or tert-butyl,and aralkyl preferably being benzyl,

but in particular compounds of the formula I in which

A is preferably as defined above under (b),

T preferably denotes an --SO-- group,

R¹ and R² are identical or different and denote hydrogen or (C₁-C₃)-alkyl,

R³ denotes hydrogen,

R⁴ and R⁵ each denote hydrogen,

R⁶ denotes hydrogen, (C₁ -C₆)-alkoxy, trifluoroethoxy,heptafluorobutoxy, benzyloxy, fluorobenzyloxy, difluorobenzyloxy,trifluorobenzyloxy, amino, ethyl or methyl, nitro, cyano or chlorine,

R⁹ denotes hydrogen,

R⁷ and R⁸ are identical and form, together with the nitrogen to whichthey are bonded, a pyrrolidine, morpholine, piperidine or piperazinering, or denote hydrogen, methyl or ethyl.

Alkyl groups alone or as part of another group (for example alkoxy,alkoxycarbonyl, alkylmercapto, alkylsulfinyl, alkylsulfonyl, aralkyl oralkanoyl) are straight-chain or branched and are, for example, methyl,ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-butyl, n-pentyl,isopentyl or n-hexyl.

Preferred (C₁ -C₆)-alkoxy groups are methoxy or ethoxy.

Preferred (C₁ -C₆)-alkoxycarbonyl groups are methoxycarbonyl orethoxycarbonyl. (C₆ -C₁₂)-aryl-(C₁ -C₆)-alkoxy is preferably understoodto mean benzyloxy.

Preferred (C₁ -C₆)-alkanoyl groups are formyl or acetyl.

Examples of (C₃ -C₈)-cycloalkyl groups are cyclopropyl cyclobutyl,cyclopentyl and cyclohexyl, and preferred (C₃ -C₆)-cycloalkyl groups arecyclopentyl or cyclohexyl.

Examples of aryl are phenyl, naphthyl or p-biphenylyl, and phenyl ispreferred. Corresponding statements apply to radicals derived therefrom,such aralkyl, aryloxy, aralkyloxy and aroyl. (C₁ -C₉)-Heteroaryl isdefined as radicals of 5- or 6-membered monocyclic, or 9- or 10-memberedbicyclic, heteroaromatic compounds having at least one carbon atom, 1 to4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members, and aredefined, for example, in Katritzky, Lagowski, Chemistry of theHeterocycles, Berlin, Heidelberg 1968, pages 3 to 5. Examples ofmonocyclic heteroaromatic compounds are thiophene, furan, pyrrole,imidazole, pyrazole, pyridine, tetrazole, pyrazine, pyrimidine,pyridazine, 1,2,4-triazole, thiazole, isothiazole, oxazole andisoxazole. Examples of bicyclic heteroaromatic compounds arebenzothiophene, benzofuran, indole, isoindole, indazole, benzimidazole,quinoline, isoquinoline, phthalazine, quinoxaline, quinazpline andcinnoline.

Halogen is fluorine, chlorine, bromine or iodine. Fluorine and chlorineare preferred.

Particularly suitable salts are salts with physiologically toleratedacids and alkali metal and alkaline earth metal salts and salts withphysiologically tolerated amines, which are formed by, for example,reaction with HCl, H₂ SO₄, phosphoric acid, alicyclic, aromatic orheteroaromatic carboxylic or sulfonic acids, with methionine,tryptophan, lysine, arginine or the like.

R³ preferably represents hydrogen, (C₁ -C₆)-alkylcarbamoyl or a radicalof the formula VI

    --(CO--O--).sub.p (CR.sup.11 R.sup.12 --O--).sub.q W--B    (VI)

in which p denotes 0 or 1, q denotes 0 or 1, W denotes a bond or --CO--,--CR¹³ R¹⁴ -- or --CO--CR¹³ R¹⁴ --, and B denotes hydrogen, an acylradical or an optionally substituted alkyl radical.

R¹¹ and R¹² are identical or different and denote hydrogen, (C₁-C₆)-alkyl, (C₃ -C₈)-cycloalkyl, (C₇ -C₁₁)aralkyl or (C₆ -C₁₂)-aryl.

B and R¹¹ can also together represent a --[CH₂ ]_(r) -chain with r=3, 4or 5 - preferably 4 - it being possible for one hydrogen atom on each ofone or more of the CH₂ groups to be replaced by OH, protected OH, amino,acylamino and/or halogen. A radical having a substituted --[CH₂]r--chain is preferably a glycosyl radical which is, where appropriate,partially or completely protected with protective groups customary incarbohydrate chemistry and which is derived from a glycopyranose,glycofuranose or oligosaccharide.

Both α- and β-glycosidic linkage of the glycosyl radical is possible.

It can be, for example, a glycofuranosyl or glycopyranosyl radicalderived from naturally occurring aldotetroses, aldopentoses,aldohexoses, ketopentoses, deoxyaldoses, aminoaldoses andoligosaccharides, such as di- and trisaccharides, as well asstereoisomers thereof.

These glycosyl radicals are derived, in particular, from natural D- orL-monosaccharides which occur in microorganisms, plants, animals orhumans, such as ribose (Rib), arabinose (Ara), xylose (Xyl), lyxose(Lyx), allose (All), altrose (Alt), glucose (Glc), mannose (Man), gulose(Gul), idose (Ido), galactose (Gal), talose (Tal), erythrose (Ery),threose (Thr), psicose (Psi), fructose (Fru), sorbose (Sor), tagatose(Tag), xylulose (Xyu), fucose (Fuc), rhamnose (Rha), olivose (Oli),oliose (Olo), mycarose (Myc), rhodosamine (RN), N-acetylglucosamine(GlcNAc), N-acetylgalactosamine (GalNAc), N-acetylmannosamine (ManNAc)or disaccharides, such as maltose (Mal), lactose (Lac), cellobiose(Cel), gentibiose (Gen), N-acetyllactosamine (LacNAc), chitobiose(Chit), β-galactopyranosyl-(1->3)-N-acetylgalactosamine and theβ-galactopyranosyl-(1->3)- or -(1->4)-N-acetylglucosamine, as well assynthetic derivatives thereof, such as 2-deoxy-, 2-amino-, 2-acetamido-or 2-halogeno-, preferably bromo- or iodo-, sugars.

Protective groups customary in carbohydrate chemistry are to beunderstood to be, for example, the (C₁ -C₁₀)-acyl protective groups suchas (C₁ -C₆)-alkanoyl (for example acetyl, trichloroacetyl andtrifluoroacetyl), benzoyl or p-nitrobenzoyl, as well as optionallymodified methyl, methyloxymethyl, benzyl, tetrahydropyranyl,benzylidene, isopropylidene or trityl groups, preference being given inthis connection to the acyl protective groups, especially the acetyl(Ac) group.

(a) If p and q are 0, the radicals preferably have the followingmeanings:

W is a bond or denotes --CO--, --CR¹³ R¹⁴ -- or --CO--CR¹³ R¹⁴. Bdenotes hydrogen (only if W is not a bond), (C₁ -C₁₀)alkyl; (C₂-C₁₂)-alkenyl; (C₃ -C₁₂)-cycloalkyl; (C₆ -C₁₂)-aryl which is optionallysubstituted by 1, 2 or 3 identical or different radicals from the seriescomprising (C₁ -C₄)-alkyl, chlorine, bromine, fluorine, nitro,trifluoromethyl, (C₁ -C₄)-alkoxy and hydroxyl; --(CH₂)_(s)--CH(NH₂)--R¹⁵ with s=1-9; the acyl radical of an amino acid, or (C₁-C₆)-alkyl which is substituted by up to 4 identical or differentradicals from the series comprising F, Cl or Br.

R¹³ and R¹⁴ are identical or different and denote hydrogen, (C₁-C₆)-alkyl, (C₁ -C₆)-alkoxy, (C₃ -C₈)cycloalkyl, (C₇ -C₁₁)-aralkyl, (C₆-C₁₂)-aryl or pyridyl, or R¹³ and R¹⁴ together represent --[CH₂ ]₄ --,--[CH₂ ]₅ -- or --[CH₂ ]₆ --, in which 1 or 2 CH₂ groups can be replacedby 0.

R¹⁵ denotes hydrogen or (C₁ -C₁₀)-alkyl.

(b) If q is 1, W and B are as defined above under (a). Furthermore, Wcan denote --CO--O-- and --CO--O--CR¹³ R¹⁴ --, with R¹³ and R¹⁴ havingthe abovementioned meanings. B can also represent hydrogen in the casewhere W=bond.

(c) If P is 1 and q is 0, W represents a bond or denotes --CR¹³ R¹⁴ --,with R¹³ and R¹⁴ having the meanings as under (a). B is defined as under(a) but cannot represent the acyl radical of an aminoacid. Furthermore,--CO--O--W--B can represent other N^(im) protective groups which are ofthe urethane type but no embraced by the abovementioned definition (cf.,for example, Hubbuch, Kontakte Merck 3/79 14-23; Bullesbach, KontakteMerck 1/80 23-35).

An optionally substituted (C₆ -C₁₂)-aryl radical (see above under (a))is to be understood to be, for example, phenyl, (o-, m-, p-)tolyl, (o-,m-, p-)ethylphenyl, 2-ethyl-tolyl, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl,(o-, m- or p-)propylphenyl, 2-propyl-(m- or p-)tolyl,4-isopropyl2,6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4-, 2,3,6- or2,4,5-)trimethylphenyl, (o-, m- or p-)fluorophenyl, (o-, m- orp-trifluoromethyl)phenyl, 4-fluoro-2,5-xylyl, (2,4-2,5-, 2,6-, 3,4- or3,5-)difluorophenyl, (o-, m- or p-)chlorophenyl, 2-chloro-p-tolyl, (3-,4-, 5- or 6-)chlorotolyl, 4-chloro-2-propylphenyl,2-isopropyl-4-chlorophenyl, 4-chloro-3,5-xylyl, (2,3-, 2,4-, 2,5-, 2,6-or 3,5-)dichlorophenyl, 4-chloro-3-fluorophenyl, (3- or4-)chloro-2-fluorophenyl, (o-, m- or p-)trifluoromethylphenyl, (o-, m-or p-)ethoxyphenyl, (4- or 5-)chloro-2-methoxyphenyl, 2,4-dichloro-(5-or 6-)methylphenyl or (o-, m- or p-)methoxyphenyl.

Examples of (C₁ -C₁₀)-alkyl are methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl and decyl or their isomeric forms.

(C₃ -C₁₂)-cycloalkyl includes alkyl-substituted cycloalkyl and bi- andpolycyclic systems. It is to be understood to include, for example:cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl,2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl,2-methylcyclobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl,cyclopentyl, 2,2-dimethylcyclophenyl, 2-pentylcyclopentyl,3-tert-butylcyclopentyl, 2,2-dimethylcyclohexyl, cycloheptyl,cyclononyl, cyclodecyl, norbornyl or adamantyl.

An acyl radical of an amino acid is to be understood to be preferablythe radical of an α-amino acid, in particular from the series ofnaturally occurring α-amino acids or their antipodes such as, forexample, H-Gly-, H-Ala-, H-Val-, H-Leu-, H-Ile-, H-Phe-, H-Lys-, H-Pro-,H-Trp-, H-Met-, H-Ser-, H-Thr-, H-Cys-, H-Tyr-, H-Asn-, H-Gln-, H-Asp-,H-Glu-, H-Arg-, H-Orn- or the corresponding radicals in the Dconfiguration.

Without intending to confine the subject matter of the inventionthereto, some urethane protective groups R³ =--CO--O--WB according tothe invention may be mentioned hereinafter: (C₁ -C₆)-alkoxycarbonyl suchas Boc; (C₃ -C₁₂)-cycloalkyloxycarbonyl such as Mboc, Iboc or Adoc;##STR5## (C₃ -C₁₂)-cycloalkyl-(C₁ -C₆)-alkoxycarbonyl such as Adpoc;##STR6## (C₆ -C₁₂)-aryl-(C₁ -C₆)-alkoxycarbonyl such as Z, Fmoc or Bpoc,##STR7## substituted Z radicals such as Moc, Ddz and Z (p-NO₂) ##STR8##and modified Z radicals such as Pyoc and corresponding radicals derivedfrom 2- and 3-picoline, all of which can be substituted as indicatedabove for (C₆ -C₁₂)-aryl. ##STR9## Preferred N^(im) protective groupsare those which can be eliminated in the presence of acids, preferablyin a pH range of about 1-6 and/or under physiological conditions.

It is surprising that compounds of the formula I with R³ ≠H are morestable than the corresponding compounds with R³ =H. In particular, theyare more stable under acid conditions as prevail, for example, in thestomach, and in the presence of water. Thus, it is possible for theexpert, by specific choice of an N^(im) protective group, to control therelease of the active compounds in such a way that this takes placeselectively at the site of action.

Any chiral carbon and sulfur atoms present can occur both in the R andin the S configuration. In such cases, compounds of the formula I existin the form of the pure enantiomers or as a stereoisomer mixture (suchas enantiomer mixture and diastereomer mixture).

The following compounds are of particular importance:

2-[4-Pyrrolidino-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[4-Piperidino-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[4-Morpholino-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[4-(N,N-Dimethylamino)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Methyl-4-pyrrolidino-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Methyl-4-piperidino-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Methyl-4-morpholino-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Methyl-4-(N,N-dimethylamino)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Amino-4-pyrrolidino-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Amino-4-piperidino-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Amino-4-morpholino-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Amino-4-(N,N-dimethylamino)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Chloro-4-pyrrolidino-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Chloro-4-piperidino-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Chloro-4-morpholino-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Chloro-4-(N,N-dimethylamino)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Chloro-6-pyrrolidino-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Chloro-6-piperidino-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Chloro-6-morpholino-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Chloro-6-(N,N-dimethylamino)-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[6-Pyrrolidino-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[6-Piperidino-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[6-Morpholino-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[6-(N,N-Dimethylamino)-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Methyl-6-pyrrolidino-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Methyl-6-piperidino-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Methyl-6-morpholino-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Methyl-6-(N,N-dimethylamino)-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Amino-6-pyrrolidino-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Amino-6-piperidino-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Amino-6-morpholino-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Methoxy-6-(N,N-dimethylamino)-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[4-Methyl-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[4-Ethoxy-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[4-Benzyloxy-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[4-Phenoxy-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[4-Isopropoxy-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[4-Methoxy-5-methyl-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[4-Ethoxy-5-methyl-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole

2-[4-Benzyloxy-5-methyl-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Methyl-4-phenoxy-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[4-Isopropoxy-5-methyl-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Chloro-4-methoxy-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Chloro-4-ethoxy-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole

2-[5-Chloro-4-isopropoxy-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[4-Benzyloxy-5-chlor-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Chloro-4-phenoxy-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[6-Methoxy-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[6-Ethoxy-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[6-Benzyloxy-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[6-Methoxy-5-methyl-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[6-Ethoxy-5-methyl-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole

2-[5-Benzyloxy-5-methyl-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Chloro-6-methoxy-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Chloro-6-ethoxy-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole

2-[4-Methylthio-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[4-Ethylthio-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Methyl-4-methylthio-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Methyl-4-ethylthio-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Chloro-4-methylthio-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Chloro-4-ethylthio-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[6-Methylthio-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[6-Ethylthio-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Methyl-6-methylthio-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[6-Ethylthio-5-methyl-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Chloro-6-methylthio-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Chloro-6-ethylthio-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-(5-Trifluormethyl-4-pyrrolidino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-(5-Trifluormethyl-4-piperidino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-(5-Trifluormethyl-4-morpholino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-[5-Trifluormethyl-4-(N,N-dimethylamino)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-(5-Fluoro-4-pyrrolidino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-(5-Fluoro-4-pyrrolidino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-(5-Fluoro-4-morpholino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-[5-Fluoro-4-(N,N-dimethylamino)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-(5-Cyano-4-pyrrolidino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-(5-Cyano-4-piperidino-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-(5-Fluoro-6-pyrrolidino-4-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-(5-Fluoro-6-piperidino-4-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-(5-Fluoro-6-morpholino-4-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-[5-Fluoro-6-(N,N-dimethylamino)-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-(5-Cyano-6-pyrrolidino-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-(5-Cyano-6-piperidino-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-(5-Cyano-6-morpholino-4-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-[5-Cyano-6-(N,N-dimethylamino)-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-(5-Nitro-6-pyrrolidino-4-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-(5-Nitro-6-piperidino-4-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-(5-Nitro-6-morpholino-4-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-[5-Nitro-6-(N,N-dimethylamino)-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-(5-Cyano-4-morpholino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-[5-Cyano-4-N,N-dimethylamino)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-(5-Nitro-4-pyrrolidino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-(5-Nitro-4-piperidino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-(5-Nitro-4-morpholino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-[5-Nitro-4-(N,N-dimethylamino)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-(5-Trifluormethyl-6-pyrrolidino-4-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-(5-Trifluormethyl-6-piperidino-4-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,

2-(5-Trifluormethyl-6-morpholino-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

2-[5-Trifluormethyl-6-(N,N-dimethylamino)-4-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,

The invention also relates to a process for the preparation of compoundsof the formula I, which comprises

(a) reaction of a compound of the formula II ##STR10## in which A, R¹,R² and R³ are as defined on pages 1 and 2 and

X¹ denotes

i. a leaving group or

ii. --SH, --S⁻ M⁺ or --SO₂ ⁻ M⁺, with M⁺ representing a cation, forexample an alkali or alkaline earth metal, ammonium or alkylammoniumion,

in particular a sodium or potassium ion, with a compound of the formulaIII ##STR11## in which X, Y, Z, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are asdefined on pages 2 and 3, and

X² denotes --SH, --S⁻ M⁺ or --SO₂ ⁻ M⁺, with M⁺ representing a cation inthe abovementioned case

i. and denotes a leaving group in the abovementioned case

ii. or

(b) reaction of a compound of the formula IV ##STR12## in which A, R¹,R² and R³ are as defined above, with a compound of the formula V##STR13## in which X, Y, Z, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are asdefined above, and R¹⁶ represents an esterifying group,

i. if desired, oxidation of (an) --S-- group(s) present whereappropriate in a compound of the formula I to (an) --SO-- or --SO₂ --group(s),

ii. if desired, oxidation of (an) --SO-- group(s) present whereappropriate in a compound of the formula I to (an) --SO₂ -- group(s),

iii. if desired, acylation, alkylation or aralkylation of a compound ofthe formula I in which R³ represents hydrogen,

iv. if desired, hydrolysis of a compound of the formula I in which R³does not denote hydrogen, and

v. conversion of a compound of the formula I, if desired, into itsphysiologically tolerated salt,

it also being possible for two or more of the measures i.-iv. to becarried out in a sequence other than that indicated.

If, in accordance with the process variant (a) which is preferred here,compounds of the formula II are reacted with compounds of the formulaIII, then X¹ or X² represents a leaving group which can be detachednucleophilically, such as Cl, Br, I, --O--SO₂ --CH₃, --O--SO₂ --CF₃ or--O--SO₂ --(C₆ H₄ --pCH₃).

The reaction of a compound of the formula II with a compound of theformula III or salts thereof is carried out in an inert solvent such as,for example, water, methylene chloride, methanol, ethanol, acetone,ethyl acetate, toluene, tetrahydrofuran, acetonitrile,dimethylformamide, dimethyl sulfoxide or mixtures of these solvents,expediently in the presence of an inorganic or organic base such as, forexample, the hydroxide, carbonate, alkoxide, hydride or amide of sodiumor potassium, or ammonia, triethylamine, tributylamine or pyridine, at-20° to +150° C., preferably at 0°-80° C.

The compounds of the formula II can be prepared in analogy to knownprocesses, for example by ring closure of appropriately substituted2,3-, 3,4- or 4,5-diaminothiophenes of the formula IV defined aboveusing appropriate sulfur compounds such as carbon disulfide (for exampleDE-A 3,132,167).

The 2,3-, 3,4- or 4,5-diaminothiophenes required for this are eitherknown from the literature or can be prepared in analogy to knownprocesses. They are obtained by, for example, reduction of appropriatelysubstituted aminonitrothiophenes.

R¹⁶ in the esters of the formula V used in process variant (b)represents an esterifying group, preferably (C₁ -C₆)-alkyl or benzyl.

The reaction of a compound of the formula IV with a compound of theformula V in process variant (b) is carried out in analogy to theprocedures described in Preston et al., Benzimidazoles and CongenericTricyclic Compounds, Part 1, New York, pages 10-13.

The compounds of the formula I obtained in this way can, if R³ denoteshydrogen, be converted into physiologically tolerated salts.

Furthermore, compounds of the formula I with T=--S-- can be converted,using suitable oxidizing agents, into those with T=--SO-- or --SO₂ --.It is also possible in the same way to oxidize --S-- groups in thesubstituents R¹, R² and R⁶ to R⁹.

This reaction is carried out in a suitable inert solvent such as, forexample, methylene chloride, chloroform, carbon tetrachloride,1,2-dichloroethane, toluene, ethyl acetate, acetic acid, trifluoroaceticacid, water, methanol, ethanol or mixtures thereof, at -20° C. to +150°C., preferably at -10° C. to +40° C.

Examples of suitable oxidizing agents are: hydrogen peroxide, peracidsand peresters such as peracetic acid, trifluoroperacetic acid,monoperphthalic acid, m-chloroperbenzoic acid and esters thereof, ozone,dinitrogen tetroxide, iodosobenzene, N-chlorosuccinimide,1-chlorobenzotriazole, sodium hypochlorite, potassium peroxodisulfate,t-butyl hypochlorite, tetrabutylammonium periodate or permanganate,sodium metaperiodate, selenium dioxide or manganese dioxide, cericammonium nitrate, chromic acid, chlorine, bromine,diazabicyclo[2.2.2]octane/bromine complex, dioxane dibromide, pyridiniumbromide perbromide, sulfuryl chloride,2-arylsulfonyl-3-aryloxaziridines, titanium tetraisopropylate/tert-butylhydroperoxide (where appropriate with the addition of dialkyl esters of(D)- or (L)-tartaric acid and a defined amount of water).

It is likewise possible to use isolated, where appropriate immobilized,oxidizing enzymes or microorganisms as oxidizing agents.

The oxidizing agents are used in equimolar amounts or, whereappropriate, in a small excess of 5-10 mol-% in the oxidation toT=--SO--, or in larger excess and/or at higher reaction temperature whenoxidation to T=--SO₂ -- is desired.

Compounds of the formula I with R³ ≠H can be prepared starting fromcompounds of the formula IV with R³ ≠H and compounds of the formula V,or by acylation, alkylation or aralkylation of compounds of the formulaI with R³ =H. The second route will be dealt with in somewhat moredetail hereinafter.

The acylation, alkylation or aralkylation of compounds of the formula Iis carried out in a manner known per se using the appropriate acylatingagents, alkylating agents or aralkylating agents in a suitable organicsolvent, as a rule at a temperature between -78° C. and the boilingpoint of the reaction mixture, where appropriate in the presence of abase.

N^(im) protective groups of the formula VI with p=0, q=1, W=bond andB=hydrogen can be introduced into compounds of the formula I (R³ =H,T=S) by, for example, hydroxyalkylation, it being possible to introduceN^(im) protective groups with R¹¹ =R¹² =hydrogen in a manner known perse (cf., for example, Eur. J. Med. Chem. 15 [1980]586; J. Med. Chem. 22[1979]1113) by hydroxymethylation using formaldehyde in an organicsolvent such as, for example, acetonitrile. The hydroxyalkylation iscarried out at a temperature between 0° C. and the boiling point of thereaction mixture, where appropriate in the presence of a base such astriethylamine.

Hydroxymethyl compounds of the formula VII ##STR14## can be converted inthe manner described in EP-A No. 176,308, page 11, into acyl derivativesof the formula VIII ##STR15## in which W-B is an acyl radical. Compoundsof the formula I with R³ =H can also be alkylated with reagents of theformula IX ##STR16## such as, for example, chloromethyl pivalate, in aknown manner, resulting in the corresponding carbonates (W=--CO--O-- or--CO--O--CR¹³ R¹⁴ --). The reaction is carried out, for example, in themanner described in EP-A No. 176,308, page 12.

Acyl radicals of amino acids are coupled in a known manner, for exampleDCC/HOBt or dialkylphosphinic anhydride method) to compounds of theformula I with R³ =H.

N^(im) protective groups of the formula VI with p=0, q=1 and R¹¹ and/orR¹² ≠ hydrogen are introduced by reacting a compound of the formula I(R³ =H, T=S) with 1 to 10 equivalents, preferably 2 to 3 equivalents, ofthe appropriate α-halogenoalkyl ester. The α-halogenoalkyl esters usedare obtained from acid halides and aldehydes by known methods (cf., forexample J. Amer. Chem. Soc. 43 [1921]660; J. Med. Chem. 23[1980]469-474).

Bromoalkyl esters are preferably used. Alternatively, it is possible totreat the anion of a compound of the formula I (R³ =H, T=S), which canbe obtained from the latter and NaH, with the α-halogenoalkyl ester.

It is also possible, in place of the α-halogenoalkyl esters, to use[1-(alkylcarbonyloxy)alkyl]pyridinium salts which are prepared inanalogy to the known [1-(arylcarbonyloxy)alkyl]pyridinium salts (cf.Angew. Chem. Suppl. 1982, 675-685) from the corresponding acyl halides,aldehydes and pyridine.

Alkylamino acetals of the formula I in which R³ represents a radical ofthe formula VI in which p is 0, q is 1 and W denotes a bond or --CR¹³R¹⁴ --, and B has the above meaning, are prepared by treating a compoundof the abovementioned formula VI in a dipolar aprotic solvent, such asdimethylformamide, with about one equivalent of NaH at about 20° to 50°C., preferably at about 25° C. The resulting anion is then reacted withabout one equivalent of a halogeno ether of the formula halogen--CR¹¹R¹² --W--B (halogen=chlorine or bromine), the reaction mixture beingstirred at about 20° to 50° C., preferably at about 25° C., for 15minutes. The halogeno ethers are known and many of them are commerciallyavailable, or they can be prepared in analogy to known compounds.

Urethanes of the formula I in which R³ represents a urethane protectivegroup of the formula VI (p=1, q=0 and W=bond or --CR¹³ R¹⁴ --) areobtained from the corresponding compounds with R³ =H by reacting thelatter, where appropriate in the presence of a base such as NaH, in asuitable solvent such as DMF, with fluoro- or chloroformic esters of theformula Cl(F)-CO-0-WB-(in analogy to the procedure described in EP-A No.176,308, page 12).

The fluoro- and chloroformates are known, and they are oftencommercially available or can be prepared by known methods.

Aralkyloxycarbonyl and alkoxycarbonyl groups can also be introducedusing the known dicarbonates, which can often be bought, such asdi-tert.-butyl dicarbonate and dibenzyl dicarbonate.

Substituted or modified Z groups in which R¹³ and/or R¹⁴ are hydrogenare prepared by reaction of the corresponding unprotected compound ofthe formula I, if necessary with the assistance of a base, with theappropriate azides or the appropriate carbonates.

The processes which can be used for the acylation of the compounds ofthe formula I (R³ =H, T=S) besides the customary standard conditions(for example acetic anhydride, triethylamine, dimethylaminopyridine) areothers such as, for example, reaction withN-[1-(arylcarbonyloxy)alkyl]pyridinium salts (disclosed in Angew. Chem.Suppl. 1982, 675-685).

For the preparation of dialkoxy derivatives of the formula I (R³ =--CR¹³R¹⁴ --B, in which R¹³ and R¹⁴ each denotes alkoxy, or together denotealkylenedioxy, and B denotes H; T=S or SO) a corresponding compound ofthe formula I with R³ =H is preferably reacted in the presence of a basewith the appropriate orthoformic esters such as trialkyl orthoformates.

Compounds of the formula III in which X² is hydroxyl can be prepared byreaction of appropriately substituted amidines with suitably substitutedβ-keto esters. For example, reaction of methoxyacetamidine hydrochloridewith the sodium salt of ethyl formylacetate yields the compound of theformula III (Y=N, X=CH, X² =OCH₃, Z=OH). The reaction of formamidineacetate with methyl 3-keto-4-methoxybutyrate analogously results in thecompound of the formula III (Y=CH, X=N, X² =OCH₃, Z=OH).

Apart from the thienoimidazole derivatives described in the examples, itis possible according to the invention also to obtain, for example, thecompounds of the general formula I or the salts thereof which are listedin the table which follows.

Abbreviations used:

methyl (Me), ethyl (Et), propyl (Pr), Butyl (Bu), hexyl (Hex), acetyl(Ac), phenyl (Ph), cyclo (c), iso (i).

                                      TABLE                                       __________________________________________________________________________    (T = SO; A as defined above under (b); R.sup.4 ; R.sup.5 and R.sup.9 each     = hydrogen)                                                                   R.sup.1                                                                           R.sup.2                                                                            R.sup.3                                                                              R.sup.6       X    Y    Z           R.sup.10                  __________________________________________________________________________    Me  Me   H      Cl            N    CR.sup.6                                                                           OR.sup.10   Me                        Me  Me   H      Cl            N    CR.sup.6                                                                           OR.sup.10   Et                        Me  Me   H      Cl            N    OR.sup.6                                                                           OR.sup.10   i-Pr                      Me  Me   H      Cl            N    OR.sup.6                                                                           OR.sup.10   CH.sub.2 Ph               Me  Me   H      Cl            N    OR.sup.6                                                                           OR.sup.10   Ph                        Me  Me   H      Cl            OR.sup.6                                                                           N    OR.sup.10   Me                        Me  Me   H      Cl            OR.sup.6                                                                           N    OR.sup.10   Et                        Me  Me   H      Cl            OR.sup.6                                                                           N    OR.sup.10   i-Pr                      Me  Me   H      Cl            OR.sup.6                                                                           N    OR.sup.10   CH.sub.2 Ph               Me  Me   H      Cl            OR.sup.6                                                                           N    OR.sup.10   Ph                        Me  Me   H      CH.sub.3      N    CR.sup.6                                                                           OR.sup.10   Me                        Me  Me   H      CH.sub.3      N    CR.sup.6                                                                           OR.sup.10   Et                        Me  Me   H      CH.sub.3      N    CR.sup.6                                                                           OR.sup.10   i-Pr                      Me  Me   H      CH.sub.3      N    CR.sup.6                                                                           OR.sup.10   Ph                        Me  Me   H      CH.sub.3      N    CR.sup.6                                                                           OR.sup.10   CH.sub.2 Ph               Me  Me   H      Me            CR.sup.6                                                                           N    OR.sup.10   Me                        Me  Me   H      Me            CR.sup.6                                                                           N    OR.sup.10   Et                        Me  Me   H      Me            CR.sup.6                                                                           N    OR.sup.10   i-Pr                      Me  Me   H      Me            CR.sup.6                                                                           N    OR.sup.10   CH.sub.2 Ph               Me  Me   H      Me            CR.sup.6                                                                           N    OR.sup.10   Ph                        Me  Me   H      H             CR.sup.6                                                                           N    OR.sup.10   Me                        Me  Me   H      H             CR.sup.6                                                                           N    OR.sup.10   Et                        Me  Me   H      H             CR.sup.6                                                                           N    OR.sup.10   i-Pr                      Me  Me   H      H             CR.sup.6                                                                           N    OR.sup.10   CH.sub.2 Ph               Me  Me   H      H             CR.sup.6                                                                           N    OR.sup.10   Ph                        Me  Me   H      H             N    CR.sup.6                                                                           OR.sup.10   Me                        Me  Me   H      H             N    CR.sup.6                                                                           OR.sup.10   Et                        Me  Me   H      H             N    CR.sup.6                                                                           OR.sup.10   i-Pr                      Me  Me   H      H             N    CR.sup.6                                                                           OR.sup.10   Ch.sub.2 Ph               Me  Me   H      H             N    CR.sup.6                                                                           OR.sup.10   Ph                        H   H    H      Cl            CR.sup.6                                                                           N    OR.sup.10   Me                        H   H    H      Cl            CR.sup.6                                                                           N    OR.sup.10   Et                        H   H    H      Cl            CR.sup. 6                                                                          N    OR.sup.10   i-Pr                      H   H    H      Cl            CR.sup.6                                                                           N    OR.sup.10   CH.sub.2 Ph               H   H    H      Cl            CR.sup.6                                                                           N    OR.sup.10   Ph                        H   H    H      Cl            N    CR.sup.6                                                                           OR.sup.10   Me                        H   H    H      Cl            N    CR.sup.6                                                                           OR.sup.10   Et                        H   H    H      Cl            N    CR.sup.6                                                                           OR.sup.10   i-Pr                      H   H    H      Cl            N    CR.sup.6                                                                           OR.sup.10   CH.sub.2 Ph               H   H    H      Cl            N    CR.sup.6                                                                           OR.sup.10   Ph                        H   H    H      H             CR.sup.6                                                                           N    OR.sup.10   Me                        H   H    H      H             CR.sup.6                                                                           N    OR.sup.10   Et                        H   H    H      H             CR.sup.6                                                                           N    OR.sup.10   i-Pr                      H   H    H      H             CR.sup.6                                                                           N    OR.sup.10   CH.sub.2 Ph               H   H    H      H             CR.sup.6                                                                           N    OR.sup.10   Ph                        H   H    H      H             N    CR.sup.6                                                                           OR.sup.10   Me                        H   H    H      H             N    CR.sup.6                                                                           OR.sup.10   Et                        H   H    H      H             N    CR.sup.6                                                                           OR.sup.10   i-Pr                      H   H    H      H             N    CR.sup.6                                                                           OR.sup.10   CH.sub.2 Ph               H   H    H      H             N    CR.sup.6                                                                           OR.sup.10   Ph                        Me  Me   H      Me            N    CR.sup.6                                                                           SR.sup.10   H                         Me  Me   H      Me            N    CR.sup.6                                                                           SR.sup.10   Me                        Me  Me   H      Me            N    CR.sup.6                                                                           SR.sup.10   Et                        Me  Me   H      Me            N    CR.sup.6                                                                           SR.sup.10   i-Pr                      Me  Me   H      Me            N    CR.sup.6                                                                           SR.sup.10   Ph                        Me  Me   H      Me            CR.sup.6                                                                           N    SR.sup.10   H                         Me  Me   H      Me            CR.sup.6                                                                           N    SR.sup.10   Me                        Me  Me   H      Me            CR.sup.6                                                                           N    SR.sup.10   Et                        Me  Me   H      Me            CR.sup.6                                                                           N    SR.sup.10   i-Pr                      Me  Me   H      Me            CR.sup.6                                                                           N    SR.sup.10   Ph                        H   H    H      Me            N    CR.sup.6                                                                           SR.sup.10   H                         H   H    H      Me            N    CR.sup.6                                                                           SR.sup.10   Me                        H   H    H      Me            N    CR.sup.6                                                                           SR.sup.10   Et                        H   H    H      Me            N    CR.sup.6                                                                           SR.sup.10   i-Pr                      H   H    H      Me            N    CR.sup.6                                                                           SR.sup.10   Ph                        H   H    H      Me            CR.sup.6                                                                           N    SR.sup.10   H                         H   H    H      Me            CR.sup.6                                                                           N    SR.sup.10   Me                        H   H    H      Me            CR.sup.6                                                                           N    SR.sup.10   Et                        H   H    H      Me            CR.sup.6                                                                           N    SR.sup.10   i-Pr                      H   H    H      Me            CR.sup.6                                                                           N    SR.sup.10   Ph                        H   H    H      H             N    CR.sup.6                                                                           SR.sup.10   H                         H   H    H      H             N    CR.sup.6                                                                           SR.sup.10   Me                        H   H    H      H             N    CR.sup.6                                                                           SR.sup.10   Et                        H   H    H      H             N    CR.sup.6                                                                           SR.sup.10   i-Pr                      H   H    H      H             N    CR.sup.6                                                                           SR.sup.10   Ph                        H   H    H      H             CR.sup.6                                                                           N    SR.sup.10   H                         H   H    H      H             CR.sup.6                                                                           N    SR.sup.10   Me                        H   H    H      H             CR.sup.6                                                                           N    SR.sup.10   Et                        H   H    H      H             CR.sup.6                                                                           N    SR.sup.10   i-Pr                      H   H    H      H             CR.sup.6                                                                           N    SR.sup.10   Ph                        Me  Me   H      H             N    CR.sup.6                                                                           SR.sup.10   H                         Me  Me   H      H             N    CR.sup.6                                                                           SR.sup.10   Me                        Me  Me   H      H             N    CR.sup.6                                                                           SR.sup.10   Et                        Me  Me   H      H             N    CR.sup.6                                                                           SR.sup.10   i-Pr                      Me  Me   H      H             N    CR.sup.6                                                                           SR.sup.10   Ph                        Me  Me   H      H             CR.sup.6                                                                           N    SR.sup.10   H                         Me  Me   H      H             CR.sup.6                                                                           N    SR.sup.10   Me                        Me  Me   H      H             CR.sup.6                                                                           N    SR.sup.10   Et                        Me  Me   H      H             CR.sup.6                                                                           N    SR.sup.10   i-Pr                      Me  Me   H      H             CR.sup.6                                                                           N    SR.sup.10   Ph                        H   H    H      H             CR.sup.6                                                                           N    NH.sub.2                              H   H    H      H             CR.sup.6                                                                           N    NHMe                                  H   H    H      H             CR.sup.6                                                                           N    NHEt                                  H   H    H      H             CR.sup.6                                                                           N    NHPh                                  H   H    H      H             CR.sup.6                                                                           N    NHCH.sub.2 Ph                         H   H    H      H             CR.sup.6                                                                           N                                                                                   ##STR17##                            H   H    H      H             CR.sup.6                                                                           N    NH-i-Pr                               H   H    H      H             CR.sup.6                                                                           N                                                                                   ##STR18##                            H   H    H      H             CR.sup.6                                                                           N                                                                                   ##STR19##                            H   H    H      H             CR.sup.6                                                                           N    NMe.sub.2                             H   H    H      H             CR.sup.6                                                                           N    NEt.sub.2                             H   H    H      H             CR.sup.6                                                                           N    N(iPr).sub.2                          H   H    H      H             CR.sup.6                                                                           N                                                                                   ##STR20##                            H   H    H      H             CR.sup.6                                                                           N                                                                                   ##STR21##                            H   H    H      H             CR.sup.6                                                                           N                                                                                   ##STR22##                            H   H    H      H             CR.sup.6                                                                           N                                                                                   ##STR23##                            H   H    H      H             CR.sup.6                                                                           N                                                                                   ##STR24##                            H   H    H      H             CR.sup.6                                                                           N                                                                                   ##STR25##                            H   H    H      H             N    CR.sup.6                                                                           NH.sub.2                              H   H    H      H             N    CR.sup.6                                                                           NHMe                                  H   H    H      H             N    CR.sup.6                                                                           NHEt                                  H   H    H      H             N    CR.sup.6                                                                           NHPh                                  H   H    H      H             N    CR.sup.6                                                                           NHCH.sub.2 Ph                         H   H    H      H             N    CR.sup.6                                                                            ##STR26##                            H   H    H      H             N    CR.sup.6                                                                           NH-i-Pr                               H   H    H      H             N    CR.sup.6                                                                            ##STR27##                            H   H    H      H             N    CR.sup.6                                                                            ##STR28##                            H   H    H      H             N    CR.sup.6                                                                           NMe.sub.2                             H   H    H      H             N    CR.sup.6                                                                           NEt.sub.2                             H   H    H      H             N    CR.sup.6                                                                           N(iPr).sub.2                          H   H    H      H             N    CR.sup.6                                                                            ##STR29##                            H   H    H      H             N    CR.sup.6                                                                            ##STR30##                            H   H    H      H             N    CR.sup.6                                                                            ##STR31##                            H   H    H      H             N    CR.sup.6                                                                            ##STR32##                            H   H    H      H             N    CR.sup.6                                                                            ##STR33##                            H   H    H      H             N    CR.sup.6                                                                            ##STR34##                            H   H    H      Cl            CR.sup.6                                                                           N    NH.sub.2                              H   H    H      Cl            CR.sup.6                                                                           N    NHMe                                  H   H    H      Cl            CR.sup.6                                                                           N    NHEt                                  H   H    H      Cl            CR.sup.6                                                                           N    NHPh                                  H   H    H      Cl            CR.sup.6                                                                           N    NHCH.sub.2 Ph                         H   H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR35##                            H   H    H      Cl            CR.sup.6                                                                           N    NH-i-Pr                               H   H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR36##                            H   H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR37##                            H   H    H      Cl            CR.sup.6                                                                           N    NMe.sub.2                             H   H    H      Cl            CR.sup.6                                                                           N    NEt.sub.2                             H   H    H      Cl            CR.sup.6                                                                           N    N(iPr).sub.2                          H   H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR38##                            H   H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR39##                            H   H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR40##                            H   H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR41##                            H   H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR42##                            H   H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR43##                            H   H    H      Cl            N    CR.sup.6                                                                           NH.sub.2                              H   H    H      Cl            N    CR.sup.6                                                                           NHMe                                  H   H    H      Cl            N    CR.sup.6                                                                           NHEt                                  H   H    H      Cl            N    CR.sup.6                                                                           NHPh                                  H   H    H      Cl            N    CR.sup.6                                                                           NHCH.sub.2 Ph                         H   H    H      Cl            N    CR.sup.6                                                                            ##STR44##                            H   H    H      Cl            N    CR.sup.6                                                                           NH-i-Pr                               H   H    H      Cl            N    CR.sup.6                                                                            ##STR45##                            H   H    H      Cl            N    CR.sup.6                                                                            ##STR46##                            H   H    H      Cl            N    CR.sup.6                                                                           NMe.sub.2                             H   H    H      Cl            N    CR.sup.6                                                                           NEt.sub.2                             H   H    H      Cl            N    CR.sup.6                                                                           N(iPr).sub.2                          H   H    H      Cl            N    CR.sup.6                                                                            ##STR47##                            H   H    H      Cl            N    CR.sup.6                                                                            ##STR48##                            H   H    H      Cl            N    CR.sup.6                                                                            ##STR49##                            H   H    H      Cl            N    CR.sup.6                                                                            ##STR50##                            H   H    H      Cl            N    CR.sup.6                                                                            ##STR51##                            H   H    H      Cl            N    CR.sup.6                                                                            ##STR52##                            H   H    H      i-Pr          CR.sup.6                                                                           N    NH.sub.2                              H   H    H      i-Pr          CR.sup.6                                                                           N    NHMe                                  H   H    H      i-Pr          CR.sup.6                                                                           N    NHEt                                  H   H    H      i-Pr          CR.sup.6                                                                           N    NHPh                                  H   H    H      i-Pr          CR.sup.6                                                                           N    NHCH.sub.2 Ph                         H   H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR53##                            H   H    H      i-Pr          CR.sup.6                                                                           N    NH-i-Pr                               H   H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR54##                            H   H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR55##                            H   H    H      i-Pr          CR.sup.6                                                                           N    NMe.sub.2                             H   H    H      i-Pr          CR.sup.6                                                                           N    NEt.sub.2                             H   H    H      i-Pr          CR.sup.6                                                                           N    N(iPr).sub.2                          H   H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR56##                            H   H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR57##                            H   H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR58##                            H   H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR59##                            H   H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR60##                            H   H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR61##                            H   H    H      i-Pr          N    CR.sup.6                                                                           NH.sub.2                              H   H    H      i-Pr          N    CR.sup.6                                                                           NHMe                                  H   H    H      i-Pr          N    CR.sup.6                                                                           NHEt                                  H   H    H      i-Pr          N    CR.sup.6                                                                           NHPh                                  H   H    H      i-Pr          N    CR.sup.6                                                                           NHCH.sub.2 Ph                         H   H    H      i-Pr          N    CR.sup.6                                                                            ##STR62##                            H   H    H      i-Pr          N    CR.sup.6                                                                           NH-i-Pr                               H   H    H      i-Pr          N    CR.sup.6                                                                            ##STR63##                            H   H    H      i-Pr          N    CR.sup.6                                                                            ##STR64##                            H   H    H      i-Pr          N    CR.sup.6                                                                           NMe.sub.2                             H   H    H      i-Pr          N    CR.sup.6                                                                           NEt.sub.2                             H   H    H      i-Pr          N    CR.sup.6                                                                           N(iPr).sub.2                          H   H    H      i-Pr          N    CR.sup.6                                                                            ##STR65##                            H   H    H      i-Pr          N    CR.sup.6                                                                            ##STR66##                            H   H    H      i-Pr          N    CR.sup.6                                                                            ##STR67##                            H   H    H      i-Pr          N    CR.sup.6                                                                            ##STR68##                            H   H    H      i-Pr          N    CR.sup.6                                                                            ##STR69##                            H   H    H      i-Pr          N    CR.sup.6                                                                            ##STR70##                            H   H    H      Et            N    CR.sup.6                                                                           NH.sub.2                              H   H    H      Et            N    CR.sup.6                                                                           NHMe                                  H   H    H      Et            N    CR.sup.6                                                                           NHEt                                  H   H    H      Et            N    CR.sup.6                                                                           NHPh                                  H   H    H      Et            N    CR.sup.6                                                                           NHCH.sub.2 Ph                         H   H    H      Et            N    CR.sup.6                                                                            ##STR71##                            H   H    H      Et            N    CR.sup.6                                                                           NH-i-Pr                               H   H    H      Et            N    CR.sup.6                                                                            ##STR72##                            H   H    H      Et            N    CR.sup.6                                                                            ##STR73##                            H   H    H      Et            N    CR.sup.6                                                                           NMe.sub.2                             H   H    H      Et            N    CR.sup.6                                                                           NEt.sub.2                             H   H    H      Et            N    CR.sup.6                                                                           N(iPr).sub.2                          H   H    H      Et            N    CR.sup.6                                                                            ##STR74##                            H   H    H      Et            N    CR.sup.6                                                                            ##STR75##                            H   H    H      Et            N    CR.sup.6                                                                            ##STR76##                            H   H    H      Et            N    CR.sup.6                                                                            ##STR77##                            H   H    H      Et            N    CR.sup.6                                                                            ##STR78##                            H   H    H      Et            N    CR.sup.6                                                                            ##STR79##                            H   H    H      Et            CR.sup.6                                                                           N    NH.sub.2                              H   H    H      Et            CR.sup.6                                                                           N    NHMe                                  H   H    H      Et            CR.sup.6                                                                           N    NHEt                                  H   H    H      Et            CR.sup.6                                                                           N    NHPh                                  H   H    H      Et            CR.sup.6                                                                           N    NHCH.sub.2 Ph                         H   H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR80##                            H   H    H      Et            CR.sup.6                                                                           N    NH-i-Pr                               H   H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR81##                            H   H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR82##                            H   H    H      Et            CR.sup.6                                                                           N    NMe.sub.2                             H   H    H      Et            CR.sup.6                                                                           N    NEt.sub.2                             H   H    H      Et            CR.sup.6                                                                           N    N(iPr).sub.2                          H   H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR83##                            H   H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR84##                            H   H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR85##                            H   H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR86##                            H   H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR87##                            H   H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR88##                            H   H    H      Me            N    CR.sup.6                                                                           NH.sub.2                              H   H    H      Me            N    CR.sup.6                                                                           NHMe                                  H   H    H      Me            N    CR.sup.6                                                                           NHEt                                  H   H    H      Me            N    CR.sup.6                                                                           NHPh                                  H   H    H      Me            N    CR.sup.6                                                                           NHCH.sub.2 Ph                         H   H    H      Me            N    CR.sup.6                                                                            ##STR89##                            H   H    H      Me            N    CR.sup.6                                                                           NH-i-Pr                               H   H    H      Me            N    CR.sup.6                                                                            ##STR90##                            H   H    H      Me            N    CR.sup.6                                                                            ##STR91##                            H   H    H      Me            N    CR.sup.6                                                                           NMe.sub.2                             H   H    H      Me            N    CR.sup.6                                                                           NEt.sub.2                             H   H    H      Me            N    CR.sup.6                                                                           N(iPr).sub.2                          H   H    H      Me            N    CR.sup.6                                                                            ##STR92##                            H   H    H      Me            N    CR.sup.6                                                                            ##STR93##                            H   H    H      Me            N    CR.sup.6                                                                            ##STR94##                            H   H    H      Me            N    CR.sup.6                                                                            ##STR95##                            H   H    H      Me            N    CR.sup.6                                                                            ##STR96##                            H   H    H      Me            N    CR.sup.6                                                                            ##STR97##                            H   H    H      Me            CR.sup.6                                                                           N    NH.sub.2                              H   H    H      Me            CR.sup.6                                                                           N    NHMe                                  H   H    H      Me            CR.sup.6                                                                           N    NHEt                                  H   H    H      Me            CR.sup.6                                                                           N    NHPh                                  H   H    H      Me            CR.sup.6                                                                           N    NHCH.sub.2 Ph                         H   H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR98##                            H   H    H      Me            CR.sup.6                                                                           N    NH-i-Pr                               H   H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR99##                            H   H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR100##                           H   H    H      Me            CR.sup.6                                                                           N    NMe.sub.2                             H   H    H      Me            CR.sup.6                                                                           N    NEt.sub.2                             H   H    H      Me            CR.sup.6                                                                           N    N(iPr).sub.2                          H   H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR101##                           H   H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR102##                           H   H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR103##                           H   H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR104##                           H   H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR105##                           H   H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR106##                           Cl  H    H      Et            N    CR.sup.6                                                                           NH.sub.2                              Cl  H    H      Et            N    CR.sup.6                                                                           NHMe                                  Cl  H    H      Et            N    CR.sup.6                                                                           NHEt                                  H   H    H      Et            N    CR.sup.6                                                                           NHPh                                  Cl  H    H      Et            N    CR.sup.6                                                                           NHCH.sub.2 Ph                         Cl  H    H      Et            N    CR.sup.6                                                                            ##STR107##                           Cl  H    H      Et            N    CR.sup.6                                                                           NH-i-Pr                               Cl  H    H      Et            N    CR.sup.6                                                                            ##STR108##                           Cl  H    H      Et            N    CR.sup.6                                                                            ##STR109##                           Cl  H    H      Et            N    CR.sup.6                                                                           NMe.sub.2                             Cl  H    H      Et            N    CR.sup.6                                                                           NEt.sub.2                             Cl  H    H      Et            N    CR.sup.6                                                                           N(iPr).sub.2                          Cl  H    H      Et            N    CR.sup.6                                                                            ##STR110##                           Cl  H    H      Et            N    CR.sup.6                                                                            ##STR111##                           Cl  H    H      Et            N    CR.sup.6                                                                            ##STR112##                           Cl  H    H      Et            N    CR.sup.6                                                                            ##STR113##                           Cl  H    H      Et            N    CR.sup.6                                                                            ##STR114##                           Cl  H    H      Et            N    CR.sup.6                                                                            ##STR115##                           Cl  H    H      Et            CR.sup.6                                                                           N    NH.sub.2                              Cl  H    H      Et            CR.sup.6                                                                           N    NHMe                                  Cl  H    H      Et            CR.sup.6                                                                           N    NHEt                                  Cl  H    H      Et            CR.sup.6                                                                           N    NHPh                                  Cl  H    H      Et            CR.sup.6                                                                           N    NHCH.sub.2 Ph                         Cl  H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR116##                           Cl  H    H      Et            CR.sup.6                                                                           N    NH-i-Pr                               Cl  H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR117##                           Cl  H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR118##                           Cl  H    H      Et            CR.sup.6                                                                           N    NMe.sub.2                             Cl  H    H      Et            CR.sup.6                                                                           N    NEt.sub.2                             Cl  H    H      Et            CR.sup.6                                                                           N    N(iPr).sub.2                          Cl  H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR119##                           Cl  H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR120##                           Cl  H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR121##                           Cl  H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR122##                           Cl  H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR123##                           Cl  H    H      Et            CR.sup.6                                                                           N                                                                                   ##STR124##                           Cl  H    H      Me            N    CR.sup.6                                                                           NH.sub.2                              Cl  H    H      Me            N    CR.sup.6                                                                           NHMe                                  Cl  H    H      Me            N    CR.sup.6                                                                           NHEt                                  Cl  H    H      Me            N    CR.sup.6                                                                           NHPh                                  Cl  H    H      Me            N    CR.sup.6                                                                           NHCH.sub.2 Ph                         Cl  H    H      Me            N    CR.sup.6                                                                            ##STR125##                           Cl  H    H      Me            N    CR.sup.6                                                                           NH-i-Pr                               Cl  H    H      Me            N    CR.sup.6                                                                            ##STR126##                           Cl  H    H      Me            N    CR.sup.6                                                                            ##STR127##                           Cl  H    H      Me            N    CR.sup.6                                                                           NMe.sub.2                             Cl  H    H      Me            N    CR.sup.6                                                                           NEt.sub.2                             Cl  H    H      Me            N    CR.sup.6                                                                           N(iPr).sub.2                          Cl  H    H      Me            N    CR.sup.6                                                                            ##STR128##                           Cl  H    H      Me            N    CR.sup.6                                                                            ##STR129##                           Cl  H    H      Me            N    CR.sup.6                                                                            ##STR130##                           Cl  H    H      Me            N    CR.sup.6                                                                            ##STR131##                           Cl  H    H      Me            N    CR.sup.6                                                                            ##STR132##                           Cl  H    H      Me            N    CR.sup.6                                                                            ##STR133##                           Cl  H    H      Me            CR.sup.6                                                                           N    NH.sub.2                              Cl  H    H      Me            CR.sup.6                                                                           N    NHMe                                  Cl  H    H      Me            CR.sup.6                                                                           N    NHEt                                  Cl  H    H      Me            CR.sup.6                                                                           N    NHPh                                  Cl  H    H      Me            CR.sup.6                                                                           N    NHCH.sub.2 Ph                         Cl  H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR134##                           Cl  H    H      Me            CR.sup.6                                                                           N    NH-i-Pr                               Cl  H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR135##                           Cl  H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR136##                           Cl  H    H      Me            CR.sup.6                                                                           N    NMe.sub.2                             Cl  H    H      Me            CR.sup.6                                                                           N    NEt.sub.2                             Cl  H    H      Me            CR.sup.6                                                                           N    N(iPr).sub.2                          Cl  H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR137##                           Cl  H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR138##                           Cl  H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR139##                           Cl  H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR140##                           Cl  H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR141##                           Cl  H    H      Me            CR.sup.6                                                                           N                                                                                   ##STR142##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N    NH.sub.2                              H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N    NHMe                                  H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N    NHEt                                  H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N    NHPh                                  H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N    NHCH.sub.2 Ph                         H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N                                                                                   ##STR143##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N    NH-i-Pr                               H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N                                                                                   ##STR144##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N                                                                                   ##STR145##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N    NMe.sub.2                             H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N    NEt.sub.2                             H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N    N(iPr).sub.2                          H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N                                                                                   ##STR146##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N                                                                                   ##STR147##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N                                                                                   ##STR148##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N                                                                                   ##STR149##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N                                                                                   ##STR150##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          CR.sup.6                                                                           N                                                                                   ##STR151##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                           NH.sub.2                              H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                           NHMe                                  H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                           NHEt                                  H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                           NHPh                                  H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                           NHCH.sub.2 Ph                         H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                            ##STR152##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                           NH-i-Pr                               H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                            ##STR153##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                            ##STR154##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                           NMe.sub.2                             H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                           NEt.sub.2                             H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                           N(iPr).sub.2                          H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                            ##STR155##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                            ##STR156##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                            ##STR157##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                            ##STR158##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                            ##STR159##                           H   H    CO.sub.2 t-Bu                                                                        i-Pr          N    CR.sup.6                                                                            ##STR160##                           H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup.6                                                                           NH.sub.2                              H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup.6                                                                           NHMe                                  H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup.6                                                                           NHEt                                  H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup.6                                                                           NHPh                                  H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup.6                                                                           NHCH.sub.2 Ph                         H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup.6                                                                            ##STR161##                           H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup.6                                                                           NH-i-Pr                               H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup.6                                                                            ##STR162##                           H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup.6                                                                            ##STR163##                           H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup.6                                                                           NMe.sub.2                             H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup.6                                                                           NEt.sub.2                             H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup.6                                                                           N(iPr).sub.2                          H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup.6                                                                            ##STR164##                           H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup.6                                                                            ##STR165##                           H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup.6                                                                            ##STR166##                           H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup.6                                                                            ##STR167##                           H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup. 6                                                                           ##STR168##                           H   H    CO.sub.2 t-Bu                                                                        Et            N    CR.sup.6                                                                            ##STR169##                           H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N    NH.sub.2                              H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N    NHMe                                  H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N    NHEt                                  H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N    NHPh                                  H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N    NHCH.sub.2 Ph                         H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N                                                                                   ##STR170##                           H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N    NH-i-Pr                               H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N                                                                                   ##STR171##                           H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N                                                                                   ##STR172##                           H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N    NMe.sub.2                             H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N    NEt.sub.2                             H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N    N(iPr).sub.2                          H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N                                                                                   ##STR173##                           H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N                                                                                   ##STR174##                           H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N                                                                                   ##STR175##                           H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N                                                                                   ##STR176##                           H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N                                                                                   ##STR177##                           H   H    CO.sub.2 t-Bu                                                                        Et            CR.sup.6                                                                           N                                                                                   ##STR178##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                           NH.sub.2                              H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                           NHMe                                  H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                           NHEt                                  H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                           NHPh                                  H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                           NHCH.sub.2 Ph                         H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                            ##STR179##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                           NH-i-Pr                               H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                            ##STR180##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                            ##STR181##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                           NMe.sub.2                             H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                           NEt.sub.2                             H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                           N(iPr).sub.2                          H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                            ##STR182##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                            ##STR183##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                            ##STR184##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                            ##STR185##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                            ##STR186##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      N    CR.sup.6                                                                            ##STR187##                           H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                           NH.sub.2                              H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                           NHMe                                  H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                           NHEt                                  H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                           NHPh                                  H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                           NHCH.sub.2 Ph                         H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                            ##STR188##                           H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                           NH-i-Pr                               H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                            ##STR189##                           H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                            ##STR190##                           H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                           NMe.sub.2                             H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                           NEt.sub.2                             H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                           N(iPr).sub.2                          H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                            ##STR191##                           H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                            ##STR192##                           H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                            ##STR193##                           H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                            ##STR194##                           H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                            ##STR195##                           H   H    CO.sub.2 t-Bu                                                                        Me            N    CR.sup.6                                                                            ##STR196##                           H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N    NH.sub.2                              H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N    NHMe                                  H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N    NHEt                                  H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N    NHPh                                  H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N    NHCH.sub.2 Ph                         H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N                                                                                   ##STR197##                           H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N    NH-i-Pr                               H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N                                                                                   ##STR198##                           H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N                                                                                   ##STR199##                           H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N    NMe.sub.2                             H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N    NEt.sub.2                             H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N    N(iPr).sub.2                          H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N                                                                                   ##STR200##                           H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N                                                                                   ##STR201##                           H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N                                                                                   ##STR202##                           H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N                                                                                   ##STR203##                           H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N                                                                                   ##STR204##                           H   H    CO.sub.2 t-Bu                                                                        Me            CR.sup.6                                                                           N                                                                                   ##STR205##                           H   H    H      NH.sub.2      CR.sup.6                                                                           N    NH.sub.2                              H   H    H      NH.sub.2      CR.sup.6                                                                           N    NHMe                                  H   H    H      NH.sub.2      CR.sup.6                                                                           N    NHEt                                  H   H    H      NH.sub.2      CR.sup.6                                                                           N    NHPh                                  H   H    H      NH.sub.2      CR.sup.6                                                                           N    NHCH.sub.2 Ph                         H   H    H      NH.sub.2      CR.sup.6                                                                           N                                                                                   ##STR206##                           H   H    H      NH.sub.2      CR.sup.6                                                                           N    NH-i-Pr                               H   H    H      NH.sub.2      CR.sup.6                                                                           N                                                                                   ##STR207##                           H   H    H      NH.sub.2      CR.sup.6                                                                           N                                                                                   ##STR208##                           H   H    H      NH.sub.2      CR.sup.6                                                                           N    NMe.sub.2                             H   H    H      NH.sub.2      CR.sup.6                                                                           N    NEt.sub.2                             H   H    H      NH.sub.2      CR.sup.6                                                                           N    N(iPr).sub.2                          H   H    H      NH.sub.2      CR.sup.6                                                                           N                                                                                   ##STR209##                           H   H    H      NH.sub.2      CR.sup.6                                                                           N                                                                                   ##STR210##                           H   H    H      NH.sub.2      CR.sup.6                                                                           N                                                                                   ##STR211##                           H   H    H      NH.sub.2      CR.sup.6                                                                           N                                                                                   ##STR212##                           H   H    H      NH.sub.2      CR.sup. 6                                                                          N                                                                                   ##STR213##                           H   H    H      NH.sub.2      CR.sup.6                                                                           N                                                                                   ##STR214##                           H   H    H      NH.sub.2      N    CR.sup.6                                                                           NH.sub.2                              H   H    H      NH.sub.2      N    CR.sup.6                                                                           NHMe                                  H   H    H      NH.sub.2      N    CR.sup.6                                                                           NHEt                                  H   H    H      NH.sub.2      N    CR.sup.6                                                                           NHPh                                  H   H    H      NH.sub.2      N    CR.sup.6                                                                           NHCH.sub.2 Ph                         H   H    H      NH.sub.2      N    CR.sup.6                                                                            ##STR215##                           H   H    H      NH.sub.2      N    CR.sup.6                                                                           NH-i-Pr                               H   H    H      NH.sub.2      N    CR.sup.6                                                                            ##STR216##                           H   H    H      NH.sub.2      N    CR.sup.6                                                                            ##STR217##                           H   H    H      NH.sub.2      N    CR.sup.6                                                                           NMe.sub.2                             H   H    H      NH.sub.2      N    CR.sup.6                                                                           NEt.sub.2                             H   H    H      NH.sub.2      N    CR.sup.6                                                                           N(iPr).sub.2                          H   H    H      NH.sub.2      N    CR.sup.6                                                                            ##STR218##                           H   H    H      NH.sub.2      N    CR.sup.6                                                                            ##STR219##                           H   H    H      NH.sub.2      N    CR.sup.6                                                                            ##STR220##                           H   H    H      NH.sub.2      N    CR.sup.6                                                                            ##STR221##                           H   H    H      NH.sub.2      N    CR.sup.6                                                                            ##STR222##                           H   H    H      NH.sub.2      N    CR.sup.6                                                                            ##STR223##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N    NH.sub.2                              H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N    NHMe                                  H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N    NHEt                                  H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N    NHPh                                  H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N    NHCH.sub.2 Ph                         H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N                                                                                   ##STR224##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N    NH-i-Pr                               H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N                                                                                   ##STR225##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N                                                                                   ##STR226##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N    NMe.sub.2                             H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N    NEt.sub.2                             H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N    N(iPr).sub.2                          H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N                                                                                   ##STR227##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N                                                                                   ##STR228##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N                                                                                   ##STR229##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N                                                                                   ##STR230##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N                                                                                   ##STR231##                           H   H    CO.sub.2 t-Bu                                                                        NH.sub.2      CR.sup.6                                                                           N                                                                                   ##STR232##                           Cl  H    H      Cl            CR.sup.6                                                                           N    NH.sub.2                              Cl  H    H      Cl            CR.sup.6                                                                           N    NHMe                                  Cl  H    H      Cl            CR.sup.6                                                                           N    NHEt                                  Cl  H    H      Cl            CR.sup.6                                                                           N    NHPh                                  Cl  H    H      Cl            CR.sup.6                                                                           N    NHCH.sub.2 Ph                         Cl  H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR233##                           Cl  H    H      Cl            CR.sup.6                                                                           N    NH-i-Pr                               Cl  H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR234##                           Cl  H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR235##                           Cl  H    H      Cl            CR.sup.6                                                                           N    NMe.sub.2                             Cl  H    H      Cl            CR.sup.6                                                                           N    NEt.sub.2                             Cl  H    H      Cl            CR.sup.6                                                                           N    N(iPr).sub.2                          Cl  H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR236##                           Cl  H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR237##                           Cl  H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR238##                           Cl  H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR239##                           Cl  H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR240##                           Cl  H    H      Cl            CR.sup.6                                                                           N                                                                                   ##STR241##                           Cl  H    H      Cl            N    CR.sup.6                                                                           NH.sub.2                              Cl  H    H      Cl            N    CR.sup.6                                                                           NHMe                                  Cl  H    H      Cl            N    CR.sup.6                                                                           NHEt                                  Cl  H    H      Cl            N    CR.sup.6                                                                           NHPh                                  Cl  H    H      Cl            N    CR.sup.6                                                                           NHCH.sub.2 Ph                         Cl  H    H      Cl            N    CR.sup.6                                                                            ##STR242##                           Cl  H    H      Cl            N    CR.sup.6                                                                           NH-i-Pr                               Cl  H    H      Cl            N    CR.sup.6                                                                            ##STR243##                           Cl  H    H      Cl            N    CR.sup.6                                                                            ##STR244##                           Cl  H    H      Cl            N    CR.sup.6                                                                           NMe.sub.2                             Cl  H    H      Cl            N    CR.sup.6                                                                           NEt.sub.2                             Cl  H    H      Cl            N    CR.sup.6                                                                           N(iPr).sub.2                          Cl  H    H      Cl            N    CR.sup.6                                                                            ##STR245##                           Cl  H    H      Cl            N    CR.sup.6                                                                            ##STR246##                           Cl  H    H      Cl            N    CR.sup.6                                                                            ##STR247##                           Cl  H    H      Cl            N    CR.sup.6                                                                            ##STR248##                           Cl  H    H      Cl            N    CR.sup.6                                                                            ##STR249##                           Cl  H    H      Cl            N    CR.sup.6                                                                            ##STR250##                           Cl  H    H      i-Pr          N    CR.sup.6                                                                           NH.sub.2                              Cl  H    H      i-Pr          N    CR.sup.6                                                                           NHMe                                  Cl  H    H      i-Pr          N    CR.sup.6                                                                           NHEt                                  Cl  H    H      i-Pr          N    CR.sup.6                                                                           NHPh                                  Cl  H    H      i-Pr          N    CR.sup.6                                                                           NHCH.sub.2 Ph                         Cl  H    H      i-Pr          N    CR.sup.6                                                                            ##STR251##                           Cl  H    H      i-Pr          N    CR.sup.6                                                                           NH-i-Pr                               Cl  H    H      i-Pr          N    CR.sup.6                                                                            ##STR252##                           Cl  H    H      i-Pr          N    CR.sup.6                                                                            ##STR253##                           Cl  H    H      i-Pr          N    CR.sup.6                                                                           NMe.sub.2                             Cl  H    H      i-Pr          N    CR.sup.6                                                                           NEt.sub.2                             Cl  H    H      i-Pr          N    CR.sup.6                                                                           N(iPr).sub.2                          Cl  H    H      i-Pr          N    CR.sup.6                                                                            ##STR254##                           Cl  H    H      i-Pr          N    CR.sup.6                                                                            ##STR255##                           Cl  H    H      i-Pr          N    CR.sup.6                                                                            ##STR256##                           Cl  H    H      i-Pr          N    CR.sup.6                                                                            ##STR257##                           Cl  H    H      i-Pr          N    CR.sup.6                                                                            ##STR258##                           Cl  H    H      i-Pr          N    CR.sup.6                                                                            ##STR259##                           Cl  H    H      i-Pr          CR.sup.6                                                                           N    NH.sub.2                              Cl  H    H      i-Pr          CR.sup.6                                                                           N    NHMe                                  Cl  H    H      i-Pr          CR.sup.6                                                                           N    NHEt                                  Cl  H    H      i-Pr          CR.sup.6                                                                           N    NHPh                                  Cl  H    H      i-Pr          CR.sup.6                                                                           N    NHCH.sub.2 Ph                         Cl  H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR260##                           Cl  H    H      i-Pr          CR.sup.6                                                                           N    NH-i-Pr                               Cl  H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR261##                           Cl  H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR262##                           Cl  H    H      i-Pr          CR.sup.6                                                                           N    NMe.sub.2                             Cl  H    H      i-Pr          CR.sup.6                                                                           N    NEt.sub.2                             Cl  H    H      i-Pr          CR.sup.6                                                                           N    N(iPr).sub.2                          Cl  H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR263##                           Cl  H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR264##                           Cl  H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR265##                           Cl  H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR266##                           Cl  H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR267##                           Cl  H    H      i-Pr          CR.sup.6                                                                           N                                                                                   ##STR268##                           H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                           NH.sub.2                              H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                           NHMe                                  H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                           NHEt                                  H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                           NHPh                                  H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                           NHCH.sub.2 Ph                         H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                            ##STR269##                           H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                           NH-i-Pr                               H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                            ##STR270##                           H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                            ##STR271##                           H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                           NMe.sub.2                             H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                           NEt.sub.2                             H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                           N(iPr).sub.2                          H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                            ##STR272##                           H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                            ##STR273##                           H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                            ##STR274##                           H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                            ##STR275##                           H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                            ##STR276##                           H   H    CO.sub.2 t-Bu                                                                        Cl            N    CR.sup.6                                                                            ##STR277##                           H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N    NH.sub.2                              H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N    NHMe                                  H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N    NHEt                                  H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N    NHPh                                  H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N    NHCH.sub.2 Ph                         H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N                                                                                   ##STR278##                           H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N    NH-i-Pr                               H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N                                                                                   ##STR279##                           H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N                                                                                   ##STR280##                           H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N    NMe.sub.2                             H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N    NEt.sub.2                             H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N    N(iPr).sub.2                          H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N                                                                                   ##STR281##                           H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N                                                                                   ##STR282##                           H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N                                                                                   ##STR283##                           H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N                                                                                   ##STR284##                           H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N                                                                                   ##STR285##                           H   H    CO.sub.2 t-Bu                                                                        Cl            CR.sup.6                                                                           N                                                                                   ##STR286##                           Me  Me   H      H             N    CR.sup.6                                                                           NH.sub.2                              Me  Me   H      H             N    CR.sup.6                                                                           NHMe                                  Me  Me   H      H             N    CR.sup.6                                                                           NHEt                                  Me  Me   H      H             N    CR.sup.6                                                                           NHPh                                  Me  Me   H      H             N    CR.sup.6                                                                           NHCH.sub.2 Ph                         Me  Me   H      H             N    CR.sup.6                                                                            ##STR287##                           Me  Me   H      H             N    CR.sup.6                                                                           NH-i-Pr                               Me  Me   H      H             N    CR.sup.6                                                                            ##STR288##                           Me  Me   H      H             N    CR.sup.6                                                                            ##STR289##                           Me  Me   H      H             N    CR.sup.6                                                                           NMe.sub.2                             Me  Me   H      H             N    CR.sup.6                                                                           NEt.sub.2                             Me  Me   H      H             N    CR.sup.6                                                                           N(iPr).sub.2                          Me  Me   H      H             N    CR.sup.6                                                                            ##STR290##                           Me  Me   H      H             N    CR.sup.6                                                                            ##STR291##                           Me  Me   H      H             N    CR.sup.6                                                                            ##STR292##                           Me  Me   H      H             N    CR.sup.6                                                                            ##STR293##                           Me  Me   H      H             N    CR.sup.6                                                                            ##STR294##                           Me  Me   H      H             N    CR.sup.6                                                                            ##STR295##                           Me  Me   H      H             CR.sup.6                                                                           N    NH.sub.2                              Me  Me   H      H             CR.sup.6                                                                           N    NHMe                                  Me  Me   H      H             CR.sup.6                                                                           N    NHEt                                  Me  Me   H      H             CR.sup.6                                                                           N    NHPh                                  Me  Me   H      H             CR.sup.6                                                                           N    NHCH.sub.2 Ph                         Me  Me   H      H             CR.sup.6                                                                           N                                                                                   ##STR296##                           Me  Me   H      H             CR.sup.6                                                                           N    NH-i-Pr                               Me  Me   H      H             CR.sup.6                                                                           N                                                                                   ##STR297##                           Me  Me   H      H             CR.sup.6                                                                           N                                                                                   ##STR298##                           Me  Me   H      H             CR.sup.6                                                                           N    NMe.sub.2                             Me  Me   H      H             CR.sup.6                                                                           N    NEt.sub.2                             Me  Me   H      H             CR.sup.6                                                                           N    N(iPr).sub.2                          Me  Me   H      H             CR.sup.6                                                                           N                                                                                   ##STR299##                           Me  Me   H      H             CR.sup.6                                                                           N                                                                                   ##STR300##                           Me  Me   H      H             CR.sup.6                                                                           N                                                                                   ##STR301##                           Me  Me   H      H             CR.sup.6                                                                           N                                                                                   ##STR302##                           Me  Me   H      H             CR.sup.6                                                                           N                                                                                   ##STR303##                           Me  Me   H      H             CR.sup.6                                                                           N                                                                                   ##STR304##                           H   H    H                                                                                     ##STR305##   N    CR.sup.6                                                                           NH.sub.2                              H   H    H      "             N    CR.sup.6                                                                           NHMe                                  H   H    H      "             N    CR.sup.6                                                                           NHEt                                  H   H    H      "             N    CR.sup.6                                                                           NHPh                                  H   H    H      "             N    CR.sup.6                                                                           NHCH.sub.2 Ph                         H   H    H      "             N    CR.sup.6                                                                            ##STR306##                           H   H    H      "             N    CR.sup.6                                                                           NH-i-Pr                               H   H    H      "             N    CR.sup.6                                                                            ##STR307##                           H   H    H      "             N    CR.sup.6                                                                            ##STR308##                           H   H    H      "             N    CR.sup.6                                                                           NMe.sub.2                             H   H    H      "             N    CR.sup.6                                                                           NEt.sub.2                             H   H    H      "             N    CR.sup.6                                                                           N(iPr).sub.2                          H   H    H      "             N    CR.sup.6                                                                            ##STR309##                           H   H    H      "             N    CR.sup.6                                                                            ##STR310##                           H   H    H      "             N    CR.sup.6                                                                            ##STR311##                           H   H    H      "             N    CR.sup.6                                                                            ##STR312##                           H   H    H      "             N    CR.sup.6                                                                            ##STR313##                           H   H    H      "             N    CR.sup.6                                                                            ##STR314##                           H   H    H                                                                                     ##STR315##   N    CR.sup.6                                                                           NH.sub.2                              H   H    H      "             N    CR.sup.6                                                                           NHMe                                  H   H    H      "             N    CR.sup.6                                                                           NHEt                                  H   H    H      "             N    CR.sup.6                                                                           NHPh                                  H   H    H      "             N    CR.sup.6                                                                           NHCH.sub.2 Ph                         H   H    H      "             N    CR.sup.6                                                                            ##STR316##                           H   H    H      "             N    CR.sup.6                                                                           NH-i-Pr                               H   H    H      "             N    CR.sup.6                                                                            ##STR317##                           H   H    H      "             N    CR.sup.6                                                                            ##STR318##                           H   H    H      "             N    CR.sup.6                                                                           NMe.sub.2                             H   H    H      "             N    CR.sup.6                                                                           NEt.sub.2                             H   H    H      "             N    CR.sup.6                                                                           N(iPr).sub.2                          H   H    H      "             N    CR.sup.6                                                                            ##STR319##                           H   H    H      "             N    CR.sup.6                                                                            ##STR320##                           H   H    H      "             N    CR.sup.6                                                                            ##STR321##                           H   H    H      "             N    CR.sup.6                                                                            ##STR322##                           H   H    H      "             N    CR.sup.6                                                                            ##STR323##                           H   H    H      "             N    CR.sup.6                                                                            ##STR324##                           H   H    H                                                                                     ##STR325##   N    CR.sup.6                                                                           NH.sub.2                              H   H    H      "             N    CR.sup.6                                                                           NHMe                                  H   H    H      "             N    CR.sup.6                                                                           NHEt                                  H   H    H      "             N    CR.sup.6                                                                           NHPh                                  H   H    H      "             N    CR.sup.6                                                                           NHCH.sub.2 Ph                         H   H    H      "             N    CR.sup.6                                                                            ##STR326##                           H   H    H      "             N    CR.sup.6                                                                           NH-i-Pr                               H   H    H      "             N    CR.sup.6                                                                            ##STR327##                           H   H    H      "             N    CR.sup.6                                                                            ##STR328##                           H   H    H      "             N    CR.sup.6                                                                           NMe.sub.2                             H   H    H      "             N    CR.sup.6                                                                           NEt.sub.2                             H   H    H      "             N    CR.sup.6                                                                           N(iPr).sub.2                          H   H    H      "             N    CR.sup.6                                                                            ##STR329##                           H   H    H      "             N    CR.sup.6                                                                            ##STR330##                           H   H    H      "             N    CR.sup.6                                                                            ##STR331##                           H   H    H      "             N    CR.sup.6                                                                            ##STR332##                           H   H    H      "             N    CR.sup.6                                                                            ##STR333##                           H   H    H      "             N    CR.sup.6                                                                            ##STR334##                           H   H    H                                                                                     ##STR335##   N    CR.sup.6                                                                           NH.sub.2                              H   H    H      "             N    CR.sup.6                                                                           NHMe                                  H   H    H      "             N    CR.sup.6                                                                           NHEt                                  H   H    H      "             N    CR.sup.6                                                                           NHPh                                  H   H    H      "             N    CR.sup.6                                                                           NHCH.sub.2 Ph                         H   H    H      "             N    CR.sup.6                                                                            ##STR336##                           H   H    H      "             N    CR.sup.6                                                                           NH-i-Pr                               H   H    H      "             N    CR.sup.6                                                                            ##STR337##                           H   H    H      "             N    CR.sup.6                                                                            ##STR338##                           H   H    H      "             N    CR.sup.6                                                                           NMe.sub.2                             H   H    H      "             N    CR.sup.6                                                                           NEt.sub.2                             H   H    H      "             N    CR.sup.6                                                                           N(iPr).sub.2                          H   H    H      "             N    CR.sup.6                                                                            ##STR339##                           H   H    H      "             N    CR.sup.6                                                                            ##STR340##                           H   H    H      "             N    CR.sup.6                                                                            ##STR341##                           H   H    H      "             N    CR.sup.6                                                                            ##STR342##                           H   H    H      "             N    CR.sup.6                                                                            ##STR343##                           H   H    H      "             N    CR.sup.6                                                                            ##STR344##                           H   H    H                                                                                     ##STR345##   CR.sup.6                                                                           N    NH.sub.2                              H   H    H      "             CR.sup.6                                                                           N    NHMe                                  H   H    H      "             CR.sup.6                                                                           N    NHEt                                  H   H    H      "             CR.sup.6                                                                           N    NHPh                                  H   H    H      "             CR.sup.6                                                                           N    NHCH.sub.2 Ph                         H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR346##                           H   H    H      "             CR.sup.6                                                                           N    NH-i-Pr                               H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR347##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR348##                           H   H    H      "             CR.sup.6                                                                           N    NMe.sub.2                             H   H    H      "             CR.sup.6                                                                           N    NEt.sub.2                             H   H    H      "             CR.sup.6                                                                           N    N(iPr).sub.2                          H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR349##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR350##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR351##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR352##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR353##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR354##                           H   H    H                                                                                     ##STR355##   CR.sup.6                                                                           N    NH.sub.2                              H   H    H      "             CR.sup. 6                                                                          N    NHMe                                  H   H    H      "             CR.sup.6                                                                           N    NHEt                                  H   H    H      "             CR.sup.6                                                                           N    NHPh                                  H   H    H      "             CR.sup.6                                                                           N    NHCH.sub.2 Ph                         H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR356##                           H   H    H      "             CR.sup.6                                                                           N    NH-i-Pr                               H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR357##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR358##                           H   H    H      "             CR.sup.6                                                                           N    NMe.sub.2                             H   H    H      "             CR.sup.6                                                                           N    NEt.sub.2                             H   H    H      "             CR.sup.6                                                                           N    N(iPr).sub.2                          H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR359##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR360##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR361##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR362##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR363##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR364##                           H   H    H                                                                                     ##STR365##   CR.sup.6                                                                           N    NH.sub.2                               H  H    H      "             CR.sup.6                                                                           N    NHMe                                  H   H    H      "             CR.sup.6                                                                           N    NHEt                                  H   H    H      "             CR.sup.6                                                                           N    NHPh                                  H   H    H      "             CR.sup.6                                                                           N    NHCH.sub.2 Ph                         H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR366##                           H   H    H      "             CR.sup.6                                                                           N    NH-i-Pr                               H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR367##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR368##                           H   H    H      "             CR.sup.6                                                                           N    NMe.sub.2                             H   H    H      "             CR.sup.6                                                                           N    NEt.sub.2                             H   H    H      "             CR.sup.6                                                                           N    N(iPr).sub.2                          H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR369##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR370##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR371##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR372##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR373##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR374##                           H   H    H                                                                                     ##STR375##   CR.sup.6                                                                           N    NH.sub.2                              H   H    H      "             CR.sup.6                                                                           N    NHMe                                  H   H    H      "             CR.sup.6                                                                           N    NHEt                                  H   H    H      "             CR.sup.6                                                                           N    NHPh                                  H   H    H      "             CR.sup.6                                                                           N    NHCH.sub.2 Ph                         H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR376##                           H   H    H      "             CR.sup.6                                                                           N    NH-i-Pr                               H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR377##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR378##                           H   H    H      "             CR.sup.6                                                                           N    NMe.sub.2                             H   H    H      "             CR.sup.6                                                                           N    NEt.sub.2                             H   H    H      "             CR.sup.6                                                                           N    N(iPr).sub.2                          H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR379##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR380##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR381##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR382##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR383##                           H   H    H      "             CR.sup.6                                                                           N                                                                                   ##STR384##                           H   H    H      OCH.sub.3     CR.sup.6                                                                           N    NH.sub.2                              H   H    H      OCH.sub.3     CR.sup.6                                                                           N    NHMe                                  H   H    H      OCH.sub.3     CR.sup.6                                                                           N    NHEt                                  H   H    H      OCH.sub.3     CR.sup.6                                                                           N    NHPh                                  H   H    H      OCH.sub.3     CR.sup.6                                                                           N    NHCH.sub.2 Ph                         H   H    H      OCH.sub.3     CR.sup.6                                                                           N                                                                                   ##STR385##                           H   H    H      OCH.sub.3     CR.sup.6                                                                           N    NH-i-Pr                               H   H    H      OCH.sub.3     CR.sup.6                                                                           N                                                                                   ##STR386##                           H   H    H      OCH.sub.3     CR.sup.6                                                                           N                                                                                   ##STR387##                           H   H    H      OCH.sub.3     CR.sup.6                                                                           N    NMe.sub.2                             H   H    H      OCH.sub.3     CR.sup.6                                                                           N    NEt.sub.2                             H   H    H      OCH.sub.3     CR.sup.6                                                                           N    N(iPr).sub.2                          H   H    H      OCH.sub.3     CR.sup.6                                                                           N                                                                                   ##STR388##                           H   H    H      OCH.sub.3     CR.sup.6                                                                           N                                                                                   ##STR389##                           H   H    H      OCH.sub.3     CR.sup.6                                                                           N                                                                                   ##STR390##                           H   H    H      OCH.sub.3     CR.sup.6                                                                           N                                                                                   ##STR391##                           H   H    H      OCH.sub.3     CR.sup.6                                                                           N                                                                                   ##STR392##                           H   H    H      OCH.sub.3     CR.sup.6                                                                           N                                                                                   ##STR393##                           H   H    H      OCH.sub.3     N    CR.sup.6                                                                           NH.sub.2                              H   H    H      OCH.sub.3     N    CR.sup.6                                                                           NHMe                                  H   H    H      OCH.sub.3     N    CR.sup.6                                                                           NHEt                                  H   H    H      OCH.sub.3     N    CR.sup.6                                                                           NHPh                                  H   H    H      OCH.sub.3     N    CR.sup.6                                                                           NHCH.sub.2 Ph                         H   H    H      OCH.sub.3     N    CR.sup.6                                                                            ##STR394##                           H   H    H      OCH.sub.3     N    CR.sup.6                                                                           NH-i-Pr                               H   H    H      OCH.sub.3     N    CR.sup.6                                                                            ##STR395##                           H   H    H      OCH.sub.3     N    CR.sup.6                                                                            ##STR396##                           H   H    H      OCH.sub.3     N    CR.sup.6                                                                           NMe.sub.2                             H   H    H      OCH.sub.3     N    CR.sup.6                                                                           NEt.sub.2                             H   H    H      OCH.sub.3     N    CR.sup.6                                                                           N(iPr).sub.2                          H   H    H      OCH.sub. 3    N    CR.sup.6                                                                            ##STR397##                           H   H    H      OCH.sub.3     N    CR.sup.6                                                                            ##STR398##                           H   H    H      OCH.sub.3     N    CR.sup.6                                                                            ##STR399##                           H   H    H      OCH.sub.3     N    CR.sup.6                                                                            ##STR400##                           H   H    H      OCH.sub.3     N    CR.sup.6                                                                            ##STR401##                           H   H    H      OCH.sub.3     N    CR.sup.6                                                                            ##STR402##                           __________________________________________________________________________

The new compounds of the formula I and their salts have valuablepharmacological properties.

They distinctly inhibit gastric acid secretion and, furthermore, have anexcellent gastrointestinal protective action.

"Gastrointestinal protection" in this connection is to be understood tobe the prevention and treatment of gastrointestinal disorders,especially inflammatory gastrointestinal disorders and lesions (such as,for example, gastric ulcer, duodenal ulcer, gastritis, and functionalgastropathy due to hyperacidity or drug-related), which can be caused,for example, by microorganisms, bacteriotoxins, drugs (for exampleantiinflammatory and antirheumatic agents), chemicals (for exampleethanol), gastric acid or stress situations.

By reason of their excellent properties, the substitutedthienoimidazoles of the formula I and their pharmacologically toleratedsalts are outstandingly suitable for use in human and veterinarymedicine, being used, in particular, for the treatment and prophylaxisof disorders of the stomach and intestines and those disorders derivingfrom excessive gastric acid secretion.

It has been found that colon H⁺ /K⁺ ATPase (cf. Gustin, Goodman, J.Biol. Chem. 256 [1981]10651-10656) is also strongly inhibited in vitroby compounds which are produced on treatment of the compounds of theformula I, according to the invention, with acid (for example withsodium acetate/HCl buffer with a pH of about 4-5.5). Transformationproducts of this type may also be formed in vivo on passage of thecompounds of the formula I through the gastrointestinal tract. Theextent to which they are formed depends on the substitution pattern andon the pH.

Colon H⁺ /K⁺ ATPase is attributed with a crucial influence on theelectrolyte balance on the intestinal mucosa. Hence, inhibitors of colonH⁺ /K⁺ ATPase, such as those mentioned above, may intervene in thisequilibrium and be used for treating disorders where the electrolytebalance is disturbed.

Hence the invention also relates to the use of compounds of the formulaI, or their acid transformation products, for the treatment of diarrhealdisorders. Examples of such disorders are inflammatory intestinaldisorders such as cholera, paratyphoid, travelers' diarrhea or othertypes of secretory diarrhea, as well as other intestinal disorders suchas ulcerative colitis and regional enteritis.

Hence the invention furthermore relates to the compounds of the formulaI, according to the invention, for use for the treatment and prophylaxisof the abovementioned disorders.

The invention likewise embraces the use of the compounds according tothe invention for the preparation of pharmaceuticals used for thetreatment and prophylaxis of the abovementioned disorders.

The invention further relates to pharmaceuticals which contain one ormore compounds of the general formula I and/or their pharmacologicallytolerated salts.

The pharmaceuticals are prepared by processes which are known per se andfamiliar to the expert. As pharmaceuticals, the pharmacologically activecompounds (=active substances) according to the invention are usedeither as such or, preferably, in combination with suitablepharmaceutical auxiliaries in the form of tablets, coated tablets,capsules, suppositories, emulsions, suspensions or solutions, with thecontent of active substance advantageously being between 0.1 and 96%.

The auxiliaries suitable for the desired pharmaceutical formulations arefamiliar to the expert on the basis of his knowledge. Besides solvents,gel-forming agents, suppository bases, tableting auxiliaries and otheractive substance vehicles, it is possible to use, for example,antioxidants, dispersing agents, emulsifiers, antifoam agents, maskingflavors, preservatives, solubilizers or colorants.

The active substances can be administered orally or parenterally, withoral administration being preferred.

In general, it has proved advantageous in human medicine, in the case oforal administration, for the active substance(s) to be administered in adaily dose of about 0.01 to about 20 mg/kg of bodyweight, whereappropriate in the form of several, preferably 1 to 4, single doses toachieve the desired result. In the case of parenteral administration,the dosages which can be used are similar or (especially in the case ofintravenous administration of the active substances) as a rule lower.Every expert will be able easily to establish, on a basis of his expertknowledge, the optimal dosage and mode of administration of the activesubstances necessary in each case.

If the compounds according to the invention and/or their salts are to beused for the treatment of the abovementioned disorders, it is alsopossible for the pharmaceutical formulations to contain one or morepharmacologically active ingredients from other groups ofpharmaceuticals, such as antibiotics, antacids, for example aluminumhydroxide, magnesium aluminate, sucralfate, bi salts; tranquilizers suchas benzodiazepines, for example diazepam; spasmolytics such as, forexample, bietamiverine, camylofin; anticholinergics such as, forexample, pirenzepine, telenzepine, oxyphencylimine, phencarbamide; localanesthetics such as, for example, tetracaine, procaine; and, whereappropriate, gastrin antagonists, enzymes, vitamins or amino acids. Fora form for oral administration, the active compounds are mixed with theadditives suitable for this purpose, such as vehicles, stabilizers orinert diluents and converted by customary methods into suitable dosageforms, such as tablets, coated tablets, hard gelatine capsules, aqueous,alcoholic or oily suspensions or aqueous, alcoholic or oily solutions.

Examples of inert vehicles which can be used are gum arabic, magnesia,magnesium carbonate, lactose, glucose or starch, especially corn starch.In this connection, formulation can be effected both as dry and wetgranules. Examples of suitable oily vehicles or solvents are vegetableand animal oils, such as sunflower oil or fish liver oil.

For subcutaneous or intravenous administration, the active compounds ortheir physiologically tolerated salts are converted into a solution,suspension or emulsion, if desired with the substances customary forthis purpose, such as solubilizers, emulsifiers or further auxiliaries.Examples of suitable solvents for the new active compounds and thecorresponding physiologically tolerated salts are: water, physiologicalsaline solutions or alcohols, for example ethanol, propanol or glycerol,as well as sugar solutions such as glucose or mannitol solutions, orelse a mixture of the various solvents mentioned.

The examples which follow serve to illustrate the invention withoutintending to confine it thereto.

EXAMPLE 12-[4-Morpholino-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole

(a) A mixture of 120 g of methoxyacetamidine hydrochloride and 300 g ofethyl formylacetate sodium salt in 1.5 1 of water was stirred at roomtemperature for 3 days.

The reaction solution was concentrated and then acidified withhydrochloric acid and extracted with hydrochloric acid and extractedwith dichloromethane. Purification by column chromatography resulted in100 g of 2-methoxymethyl-4-pyrimidone (melting point 126° C.).

(b) A suspension of 100 g of 2-methoxymethyl-4-pyrimidone and 500 ml ofphosphorus oxychloride was slowly heated until a clear solution formed.Excess phosphorus oxychloride was distilled, the residue was hydrolyzedwith ice-water, and the pH was adjusted to 10 with sodium hydroxidesolution. Extraction with dichloromethane followed by purification bycolumn chromatography resulted in 101 g of2-methoxymethyl-4-chloropyrimidine as an oil.

(c) A solution of 12 g of 2-methoxymethyl-4-chloropyrimidine and 15 mlof morpholine in 50 ml of dichloromethane was stirred at roomtemperature for 3 hours. The reaction solution was washed several timeswith water. The organic phase was dried and, after purification bycolumn chromatography, yielded 13 g of2-methoxymethyl4-morpholinopyrimidine as an oil.

(d) A solution of 24 ml of boron tribromide in 100 ml of dichloromethanewas added dropwise, at -25° C. under a nitrogen atmosphere, to asolution of 13 g of 2-methoxymethyl-4-morpholinopyrimidine in 100 ml ofdichloromethane. After 30 minutes at -25° C., the solution was left tostand at 0° C. for a further 2 hours and then poured onto ice. Thesolution was made alkaline with sodium hydroxide solution and wasextracted with dichloromethane. After drying (Na₂ SO₄) andconcentration, diethyl ether was added, and 5.5 g of2-hydroxymethyl-4-morpholinopyrimidine were obtained as a solid (meltingpoint 76°-77° C.).

(e) A solution of 5.5 g of 2-hydroxymethyl-4-morpholinopyrimidine and 17ml of thionyl chloride in 200 ml of dichloromethane was stirred at roomtemperature for 3 hours. After concentration, diethyl ether was added,and the precipitated 2-chloromethyl-4-morpholinopyrimidine hydrochloridewas filtered off (yield 6.0 g; melting point 215° C.).

(f) A mixture of 1 g of sodium methylate, 1.3 g of2-mercaptothieno[3,4-d]imidazole and 2 g of2-chloromethyl4-morpholinopyrimidine hydrochloride in 50 ml of methanolwas heated under reflux for 2 hours. The mixture was then poured ontoice-water and extracted with dichloromethane. Purification by columnchromatography resulted in 1.6 g of2-(4-morpholino-2-pyrimidinylmethylthio)thieno[3,4-d]imidazole as asolid (melting point 185° C. [decomposition]).

(g) 200 mg of m-chloroperbenzoic acid were added in portions to asuspension of 300 mg of2-(4-morpholino-2-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole in amixture of 30 ml of dichloromethane and 30 ml of sodium bicarbonatesolution at 0° C. After 30 minutes, the Na salt of2-(4-morpholino-2-pyrimidinylmethylsulfinyl)1H-thieno-[3,4-d]imidazoleseparated out between the phases and was filtered off and washed withdichloromethane (yield: 300 mg; melting point 165° C. [decomposition]).

(h) 300 mg of the Na salt of2-(4-morpholino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazolewere suspended in a mixture of 10 ml of dichloromethane and 10 ml ofwater, and the pH was adjusted to 6 with saturated ammonium chloridesolution. The aqueous phase was extracted with dichloromethane, and theorganic phase was dried (Na₂ SO₄) and concentrated. Radial layerchromatography resulted in 200 mg of2-(4-morpholino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazoleas a solid (melting point 164° C. [decomposition]).

The following compounds were obtained in an analogous manner:

EXAMPLE 2

2-[4-Piperidino-2-pyrimidinylmethylthio]-1H-thieno[3,4-d]imidazole,melting point 197° C. [decomposition]

EXAMPLE 3

2-[4-N,N-Dimethylamino-2-pyrimidinylmethylthio]-1H-thieno[3,4-d]imidazole,melting point 193° C. [decomposition]

EXAMPLE 4

2-[5-Methyl-4-morpholino-2-pyrimidinylmethylthio]-1H-thieno[3,4-d]imidazole,melting point 177° C. [decomposition]

EXAMPLE 5

2-[5-Methyl-4-piperidino-2-pyrimidinylmethylthio]-1H-thieno[3,4-d]imidazole,melting point 117° C. [decomposition]

EXAMPLE 6

2-[5-Methyl-4-piperazino-2-pyrimidinylmethylthio]-1H-thieno[3,4-d]imidazole,melting point 230° C. [decomposition]

EXAMPLE 7

2-[5-Methyl-4-(4-methylphenylamino)-2-pyrimidinylmethylthio]-1H-thieno[3,4-d]imidazole,melting point 77° C. [decomposition]

EXAMPLE 8

2-[5-Methyl-4-(4-methylphenylamino)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,melting point 115° C. [decomposition]

EXAMPLE 9

2-(5-Chloro-4-piperidino-2-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole,melting point 132° C. [decomposition]

EXAMPLE 10

2-(5-Chloro-4-piperidino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,melting point 59° C. [decomposition]

EXAMPLE 11

2-(5-Chloro-4-morpholino-2-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole,melting point 165° C. [decomposition]

EXAMPLE 12

2-(5-Chloro-4-morpholino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,melting point 81° C. [decomposition]

EXAMPLE 13

2-(5-Chloro-4-morpholino-2-pyrimidinylmethylsulfonyl)-1H-thieno[3,4-d]imidazole,melting point 155° C. [decomposition]

EXAMPLE 14

2-[5-Methyl-4-(4-methyl-1-piperazinyl)-2-pyrimidinylmethylthio]-1H-thieno[3,4-d]imidazole,melting point 159° C. [decomposition]

EXAMPLE 15

2-(5-Chloro-4-pyrrolidino-2-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole,melting point 188° C. [decomposition]

EXAMPLE 16

2-(5-Chloro-4-pyrrolidino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,melting point 86° C. [decomposition]

EXAMPLE 17

2-[5-Chloro-4-(N,N-dimethylamino)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,melting point 178° C. [decomposition]

EXAMPLE 18

2-[5-Chloro-4-(N,N-dimethylamino-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,melting point 112° C. [decomposition]

EXAMPLE 19

2-(4-Benzylpiperidino-5-chloro-2-pyrimidinylmethylsulfonyl)-1H-thieno[3,4-d]imidazole,melting point 166° C. [decomposition]

EXAMPLE 20

2-(4-Methoxy-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole

(a) 650 g of ethyl formylacetate sodium salt were dissolved in 4 1 ofcold water, and 450 g of acetamidine hydrochloride were added. After thesolution had stood at room temperature for two days it was evaporated todryness in vacuo, and the residue was extracted with hot ethanol.Concentration of the ethanolic extracts and purification by columnchromatography resulted in 240 g of 2-methyl-4-pyrimidone (melting point212° C.).

(b) 11 g of 2-methyl-4-pyrimidone were introduced into 50 ml ofphosphorus oxychloride, and the mixture was heated at 80° C. until aclear solution was produced. Excess phosphorus oxychloride was removedby distillation in vacuo, and the residue was poured into ice-water.While cooling, the solution was neutralized with potassium hydroxidesolution and extracted with dichloromethane. The organic extracts weredried (Na₂ SO₄) and concentrated in vacuo, and column chromatographyresulted in 8 g of 4-chloro-2-methylpyrimidine (melting point 50°-60°C.).

(c) 6.5 g of 4-chloro-2-methylpyrimidine were added to a solution of 1.2g of sodium in 50 ml of absolute methanol. The reaction mixture washeated under reflux for 1 hour and then concentrated in vacuo, water wasadded and extraction with diethyl ether was carried out. Columnchromatography resulted in 6 g of 4-methoxy-2methylpyrimidine as an oil.

(d) A suspension of 6 g of 4-methoxy-2-methylpyrimidine and 4 g oftrichloroisocyanuric acid in 50 ml of carbon tetrachloride was heatedunder reflux. After the reaction was complete, water was added, the pHwas adjusted to 8 to 9, and the mixture was extracted withdichloromethane. Column chromatography resulted in 4 g of2-chloromethyl-4-methoxypyrimidine as an oil.

(e) 900 mg of sodium hydride suspension (55 %) and, after 15 minutes,3.3 g of 2-chloromethyl-4-methoxypyrimidine were added to a solution of3.1 g of 2-mercaptothieno[3,4-d]imidazole in 100 ml of absolutedimethylformamide at room temperature. The reaction mixture was thenstirred at room temperature for 1 hour, poured onto ice and extractedwith dichloromethane. Drying (Na₂ SO₄) and concentration of the organicphase was followed by purification on a silica gel column, resulting in1.6 g of 2-(4-methoxy-2-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole(melting point 165° C. [decomposition]).

(f) 1.1 g of2-(4-methoxy-2-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole weredissolved in 100 ml of dichloromethane and, at -10° C., 820 mg ofm-chloroperbenzoic acid were added in portions. The mixture was thenstirred at room temperature for 15 minutes, extracted by shaking withsodium bicarbonate solution, and the organic phase was dried over sodiumsulfate and concentrated. Purification by chromatography resulted in 300mg of 2-(4-methoxy-2-pyrimidinylmethylsulfinyl)1H-thieno[3,4-d]imidazole(melting point 125° C. [decomposition]).

The following compounds were obtained in analogy to Example 20:

EXAMPLE 21

2-(4-Ethoxy-2-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole, meltingpoint 164° C. [decomposition]

EXAMPLE 22

2-(4-Ethoxy-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,melting point 115° C. [decomposition]

EXAMPLE 23

2-(4-Isopropoxy-2-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole,melting point 182° C. [decomposition]

EXAMPLE 24

2-(4-Isopropoxy-2-pyrimidinylmethylsulfinyl)-1H-thieno-[3,4-d]imidazole, melting point 118° C. [decomposition]

EXAMPLE 25

2-(6-Morpholino-4-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole

(a) A solution of 86 g of sodium in 1.5 1 of methanol was added to asolution of 250 g of methyl 4-methoxyacetoacetate and 200 g offormamidine acetate in 1.5 1 of methanol. The reaction solution washeated at 60° C. for 48 hours, then concentrated in vacuo and pouredinto ice-water. Neutralization with hydrochloric acid was followed byextraction with dichloromethane, drying over sodium sulfate andconcentration in vacuo. Purification on a silica gel column resulted in100 g of 6-hydroxy-4-methoxymethylpyrimidine (melting point 160° C.).

(b) 50 g of 6-hydroxy-4-methoxymethylpyrimidine were heated in 375 ml ofphosphorus oxychloride until a clear solution had been produced. Theexcess phosphorus oxychloride was removed by distillation in vacuo, andthe residue was poured into ice-water. Extraction with dichloromethaneand drying over sodium sulfate were followed by concentration of thesolution in vacuo. 58 g of 6-chloro-4-methoxymethylpyrimidine wereobtained as an oil which was used without further purification in thenext stage.

(c) 29 g of 6-chloro-4-methoxymethylpyrimidine were dissolved in 200 mlof tetrahydrofuran, and 32 g of morpholine were added. After 3 hours atroom temperature, the mixture was filtered with suction, and thefiltrate was concentrated in vacuo.

37 g of 6-morpholino-4-methoxymethylpyrimidine were obtained (meltingpoint 56° C.).

(d) 38 ml of 1M boron tribromide solution in CH₂ Cl₂ were addeddropwise, at 0° C., under a nitrogen atmosphere, to a solution of 5.3 gof 6-morpholino-4-methoxymethylpyrimidine in 100 ml of dichloromethane.The reaction solution was poured into ice-water, and the pH was adjustedto 13 with sodium hydroxide solution. Extraction with dichloromethanewas followed by the organic phase being dried over sodium sulfate andconcentrated in vacuo.

3 g of 4-hydroxymethyl-6-morpholinopyrimidine were obtained (meltingpoint 138° C.).

(e) A solution of 36 ml of thionyl chloride in 30 ml of dichloromethanewas added dropwise, at 0° C., to a solution of 3 g of4-hydroxymethyl-6-morpholinopyrimidine in 30 ml of dichloromethane. Thereaction solution was allowed to reach room temperature and wasconcentrated in vacuo. Addition of diethyl ether resulted inprecipitation of 3.2 g of 4-chloromethyl-6-morpholinopyrimidinehydrochloride (melting point 139° C. [decomposition]).

(f) 1 g of 4-chloromethyl-6-morpholinopyrimidine hydrochloride wasreacted with 625 mg of 2-mercaptothieno[[3,4-d]imidazole in analogy tothe description in Example 1f. 420 mg of2-(6-morpholino-4-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole wereobtained (melting point 178° C. [decomposition]).

(g) 180 mg of2-(6-morpholino-4-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole wereoxidized with m-chloroperbenzoic acid in analogy to Example 1g. 140 mgof2-(6-morpholino-4-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazolewere obtained (melting point 107° C. [decomposition]).

The following compounds were obtained in an analogous manner:

EXAMPLE 26

2-(6-Piperidino-4-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole,melting point 161° C. [decomposition].

EXAMPLE 27

2-(5-Chloro-6-piperidino-4-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole,melting point 152° C. [decomposition]

EXAMPLE 28

2-(5-Chloro-6-piperidino-4-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,melting point 89° C. [decomposition]

EXAMPLE 29

2-(5-Chloro-6-morpholino-4-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole,melting point 72° C. [decomposition]

EXAMPLE 30

2-(5-Chloro-6-morpholino-4-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,melting point 90° C. [decomposition]

EXAMPLE 31

2-(5-Methoxy-4-piperidino-2-pyrimidinylmethylsulfinyl)1H-thieno[3,4-d]imidazole

(a) When the ethyl formylacetate sodium salt described

in Example 1a is replaced by ethyl 2-methoxy-3-oxopropionate sodiumsalt, the product obtained correspondingly is5-methoxy-2-methoxymethyl-4-pyrimidinone, melting point 61° C.

When the 5-methoxy-2-methoxymethyl-4-pyrimidinone is reacted further asdescribed in Example 1b-g, the final stage obtained via intermediatestages 31b-f is 31g.

(b) 4-Chloro-5-methoxy-2-methoxymethylpyrimidine, oil

(c) 5-Methoxy-2-methoxymethyl-4-piperidinopyrimidine, oil

(d) 2-Hydroxy-5-methoxy-4-piperidinopyrimidine, melting point 102° C.

(e) 2-Chloromethyl-5-methoxy-4-piperidinopyrimidine hydrochloride,melting point 189° C. [decomposition]

(f)2-(5-Methoxy-4-piperidino-2-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole,melting point 103° C. [decomposition]

(g)2-(5-Methoxy-4-piperidino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,melting point 155° C. [decomposition]

EXAMPLE 32

2-(5-Methoxy-4-morpholino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,melting point 130° C. [decomposition]

EXAMPLE 33

2-(5-Benzyloxy-4-morpholino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,melting point 56° C. [decomposition]

EXAMPLE 34

2-[5-Benzyloxy-4-(4-benzylpiperidino)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,melting point 62° C. [decomposition]

EXAMPLE 35

2-(5-Benzyloxy-4-piperidino-2-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole,melting point 72° C. [decomposition]

EXAMPLE 36

2-[5-Benzyloxy-4-(N,N-dimethylamino)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,melting point 65° C. [decomposition]

EXAMPLE 37

2-[5-(4-Fluorobenzyloxy)-4-(4-benzylpiperidino)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,melting point 119° C. [decomposition]

EXAMPLE 38

2-[5-(4-Fluorobenzyloxy)-4-piperidino-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,melting point 110° C. [decomposition]

EXAMPLE 39

2-[5-(4-Fluorobenzyloxy)-4-morpholino-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,melting point 125° C. [decomposition]

EXAMPLE 40

2-[4-Piperidino-5-(2,2,2-trifluoroethoxy)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,melting point 168° C. [decomposition]

EXAMPLE 41

2-[4-(N,N-Dimethylamino)-5-(2,2,2-trifluoroethoxy)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,melting point 155° C. [decomposition]

EXAMPLE 42

2-[4-Morpholino-5-(2,2,2-trifluoroethoxy)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,melting point 165° C. [decomposition]

EXAMPLE 43

2-[4-Pyrrolo-5-(2,2,2-trifluoroethoxy)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,melting point 155° C. [decomposition]

EXAMPLE 44

2-[4-Piperidino-5-(4,4,4,3,3,2,2-heptafluorobutoxy)-2-pyrimidinylmethylsulfinyl]-1H-thieno[3,4-d]imidazole,melting point 172° C. [decomposition

We claim:
 1. A compound of the formula I ##STR403## in which Arepresents ##STR404## T denotes --S--, --SO-- or --SO₂ --, R¹ and R² areidentical or different and denote hydrogen, halogen, cyano, nitro,trifluoromethyl, (C₁ -C₆)-alkyl, (C₁ -C₆)-hydroxyalkyl, (C₁ -C₆)-alkoxy,(C₁ -C₄)-fluoroalkoxy, --O--CF₂ Cl--, --O--CF₂ -CHFCl, (C₁-C₆)-alkylmercapto, (C₁ -C₆)-alkylsulfinyl, (C₁ -C₆)-alkylsulfonyl, (C₁-C₆)-alkylcarbonyl, (C₁ -C₆)-alkoxycarbonyl. carbamoyl, N-(C₁-C₄)-alkylcarbamoyl, N,N-di(C₁ -C₄)-alkylcarbamoyl, (C₁-C₆)-alkylcarbonyloxy, (C₃ -C₈)-cycloalkyl, phenyl, benzyl, phenoxy,benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl,phenylsulfinyl, sulfamoyl, N-(C₁ -C₄)-alkylsulamoyl or N,N-di-(C₁-C₄)-alkylsulfamoyl, or, if A is defined as above under (a) or (c), canalso together denote --(CH₂)_(n) -- or --CH═CH--CH═CH--, with one CH₂group optionally being replaced by O, S, SO or SO₂,R³ denotes hydrogen,alkanoyl, (C₁ -C₆)-alkylcarbamoyl or another physiologically toleratedprotective group which can preferably be eliminated in an acid medium orunder physiological conditions, R⁴ and R⁵ are identical or different anddenote hydrogen or (C₁ --C₃)-alkyl, X denotes nitrogen, and Y denotesCR⁶, or X denotes CR⁶, and Y denotes nitrogen, R⁶ denotes hydrogen,halogen, (C₁ -C₆)-alkyl, trifluoromethyl, (C₁ -C₆)-alkoxy, --O--C_(p)H(2p+1-q)F_(q), (C₁ -C₆)-alkoxy-(C₁ --C₆)-alkyl, (C₆ -C₁₂)-aryl, (C₆-C₁₂)-aryl-(C₁ -C₆)-alkoxy, thiophene, furan, pyrrole, imidazole,pyrazole, pyridine, tetrazole, pyrazine, pyrimidine, pyridazine,1,2,4-triazole, thiazole, isothiazole, oxazole, isoxazole,benzothiophene, benzofuran, indole, inazole, benzimidazole, quinazoline,cinnoline, (C₁ -C₆)-aryloxy, it being possible for the correspondingaryl moiety to be optionally substituted by halogen or trifluoromethyl,or denotes cyano, nitro, (C₁ -C₆)-alkylamino, di-(C₁ -C₆)-alkylamino oramino, Z denotes NR⁷ R⁸, OR¹⁰ or SR¹⁰, R⁷ and R⁸ are identical ordifferent and denote hydrogen, (C₁ -C₆)-alkyl, C₆ -C₁₂)-aryl, (C₇-C₁₃)-aralkyl or (C₃ -C₆)-cycloalkyl, or represent, together with thenitrogen to which they are bonded, azetidino, pyrrolidino, piperidino,piperazino, morpholino or N-(C₁ -C₄)-alkylpiperazino, each of which isoptionally substituted by one or two identical or different (C₁-C₆)-alkyl groups, R⁹ denotes hydrogen, halogen, (C₁ -C₃)-alkyl, C₁-C₄)-alkoxy, benzyloxy or (C₁ -C₇)-alkoxy-(C₁ -C₃)-alkyl, R¹⁰ denoteshydrogen, (C₁ -C₄)-alkyl, (C₇ -C₁₃)-aralkyl, (C₆ -C₁₂)-aryl, vinyl,allyl or a substituted alkyl radical of the formula C_(p) H.sub.(2p+1-q)F_(q), n is 3 or 4, p is 1, 2, 3 or 4, and q is 1 to (2p+1), orits physiologically tolerated salt.
 2. A compound of the formula I asclaimed in claim 1, in which R⁹ denotes hydrogen, or its physiologicallytolerated salt.
 3. A compound of the formula I as claimed in claim 1 inwhich A is as defined in claim 1 under (b), or its physiologicallytolerated salt.
 4. A compound of the formula I as claimed in claim 1, inwhich T represents --SO--, or its physiologically tolerated salt.
 5. Acompound of the formula I as claimed in claim 1, in which R¹ and R² areidentical or different and denote hydrogen, (C₁ -C₃)-alkyl, halogen, (C₁-C₄)-alkoxy or (C₁ -C₄)alkoxycarbonyl,R³ is as defined in claim 1, R⁴and R⁵ each denote hydrogen, and R⁶ denotes amino, hydrogen, halogen,(C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy, --O--C_(p) H(2p+1-q)F_(q),(C₆-C₁₂)-aryloxy, (C₆ -C₁₂)-aryl-(C₁ -C₆)-alkoxy, it being possible for thecorresponding aryl moiety to be optionally substituted by halogen ortrifluoromethyl, or denotes cyano, nitro, (C₁ -C₆)-alkylamino, di-(C₁-C₆)-alkylamino or (C₁ -C₆)-alkoxy-(C₁ -C₃)-alkyl; R⁷ and R⁸ areidentical or different and denote hydrogen, (C₁ -C₆)-alkyl, (C₃-C₆)-cycloalkyl or phenyl, or the latter represent, together with thenitrogen to which they are bonded, azetidino, pyrrolidino, piperidino,piperazino, morpholino or N-(C₁ -C₄)-alkylpiperazino, and R⁹ and R¹⁰ areas defined in claim 1, or its physiologically tolerated salt.
 6. Acompound of the formula I as claimed in claim 1, in whichR¹ and R² areidentical or different and denote hydrogen or (C₁ -C₃)-alkyl, R³ denoteshydrogen, R⁴ and R⁵ each denote hydrogen, R⁶ denotes hydrogen, amino,(C₁ -C₆)-alkoxy, trifluoroethoxy, heptafluorobutoxy, benzyloxy,fluorobenzyloxy, difluorobenzyloxy, trifluorobenzyloxy, chlorine, nitro,cyano, methyl or ethyl, R⁹ denotes hydrogen, R⁷ and R⁸ are identical ordifferent and denote hydrogen, phenyl or (C₁ -C₆)-alkyl, or the latterrepresent, together with the nitrogen to which they are bonded,azetidino, piperidino, pyrrolidino, morpholino, piperazino or N-(C₁-C₄)-alkylpiperazino, and R¹⁰ denotes (C₁ -C₄)-alkyl, phenyl or benzyl,or its physiologically tolerated salt.
 7. A method of treatinggastrointestinal disorders as well as diseases which derive from anincrease in gastric acid secretion, which comprises administration of aneffective amount of a compound of the formula I as claimed in claim 1,or a physiologically tolerated salt thereof.
 8. A pharmaceuticalformulation for treating gastrointestinal disorders as well as diseaseswhich derive from an increase in gastric acid secretion, containing aneffective amount of a compound of the formula I as claimed in claim 1,or a physiologically tolerated salt thereof, and a pharmaceuticallyacceptable vehicle.